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Sample records for cd40mab adjuvant induces

  1. Does lipophilicity per se induce adjuvant effects?

    DEFF Research Database (Denmark)

    Hansen, Jitka Stilund; Larsen, Søren Thor; Poulsen, Lars K.

    2007-01-01

    Anthopogenically introduced substances and pollutants are suspected to promote sensitization and development of allergic airway diseases, that is, acting as adjuvants. Lipophilicity may serve as an immunological warning signal, promoting adjuvant effects. Whether the lipophilicity of an inhaled...... respiratory patterns were significantly affected in the MP groups. The OVA + Al(OH)3 group had a significantly higher IgG1 and IgE production, as well as higher eosinophil infiltration in the BAL fluid. These studies showed that effects of adjuvants not are necessarily due to their lipophilicity; that is...

  2. Assessment of side effects induced by injection of different adjuvant/antigen combinations in rabbits and mice

    NARCIS (Netherlands)

    Leenaars, P.P.A.M.; Koedam, M.A.; Wester, P.W.; Baumans, V.; Claassen, E.; Hendriksen, C.F.M.

    1998-01-01

    We evaluated the side effects induced by injection of Freund's adjuvant (FA) and alternative adjuvants combined with different antigens. Rabbits and mice were injected subcutaneously, intramuscularly (rabbits) and intraperitoneally (mice) with different adjuvants (FA, Specol, RIBI, TiterMax,

  3. Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation

    NARCIS (Netherlands)

    Brok, M.H. den; Bull, C.; Wassink, M.; Graaf, A.M.A. de; Wagenaars, J.A.L.; Minderman, M.; Thakur, M.; Amigorena, S.; Rijke, E.O.; Schrier, C.C.; Adema, G.J.

    2016-01-01

    Saponin-based adjuvants (SBAs) are being used in animal and human (cancer) vaccines, as they induce protective cellular immunity. Their adjuvant potency is a factor of inflammasome activation and enhanced antigen cross-presentation by dendritic cells (DCs), but how antigen cross-presentation is

  4. Agmatine ameliorates adjuvant induced arthritis and inflammatory cachexia in rats.

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    Taksande, Brijesh G; Gawande, Dinesh Y; Chopde, Chandrabhan T; Umekar, Milind J; Kotagale, Nandkishor R

    2017-02-01

    The present study investigated the pharmacological effect of agmatine in Complete Freud Adjuvant (CFA) induced arthritis and cachexia in rats. The rats were injected with CFA (0.1ml/rat) to induced symptoms of arthritis. Day 8 onwards of CFA administration, rats were injected daily with agmatine for next 7days, and arthritis score, body weights and food intake were monitored daily (g). Since cachexia is known to produce severe inflammation, malnutrition and inhibition of albumin gene expression, we have also monitored the total proteins, albumin, TNF-α and IL-6 levels in arthritic rats and its modulation by agmatine. In the present study, CFA treated rats showed a progressive reduction in both food intake and body weight. In addition analysis of blood serum of arthritis animals showed a significant reduction in proteins and albumin and significant elevation in tumor necrosis factor (TNF)-α and Interleukins (IL)-6. Chronic agmatine (20-40mg/kg, ip) treatment not only attenuated the signs of arthritis but also reverses anorexia and body weight loss in CFA treated rats. In addition, agmatine restored total protein and albumin and reduces TNF-α and IL-6 levels in arthritis rats. These results suggest that agmatine administration can prevent the body weights loss and symptoms of arthritis via inhibition of inflammatory cytokines. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  5. Psidium guajava leaves decrease arthritic symptoms in adjuvant-induced arthritic rats

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    Hanif Nasiatul Baroroh

    2016-04-01

    Psidium guajava leaf extract is effective in decreasing the inflammatory response and arthritic symptoms in rats with adjuvant-induced arthritis. Psidium guajava leaves can be developed into an alternative anti-arthritis treatment.

  6. Evidence Refuting the Existence of Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA)

    DEFF Research Database (Denmark)

    Ameratunga, Rohan; Gillis, David; Gold, Michael

    2017-01-01

    Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) was described in 2011. Over time the condition and its triggers have broadened to include several autoimmune disorders, the macrophagic myofasciitis syndrome, the Gulf war syndrome, the sick building syndrome, siliconosis...

  7. A Controlled Study Using Acupuncture as an Adjuvant to Treat Chemotherapy-Induced Nausea and Vomiting

    National Research Council Canada - National Science Library

    Lao, Lixing

    2001-01-01

    ...) on nausea and vomiting induced by chemotherapy in cancer patients. The primary aim of this study is to evaluate the usefulness of EA as an adjuvant on N/V in chemotherapy patients who do not respond to conventional antiemetics...

  8. Accounting for adjuvant-induced artifacts in the characterization of vaccine formulations by polyacrylamide gel electrophoresis.

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    Jakob, Virginie; Brunner, Livia; Barnier-Quer, Christophe; Blust, Molly; Collin, Nicolas; Carter, Lauren; Carter, Darrick; Rausch, Kelly M; Fox, Christopher B

    2017-04-01

    Several vaccine adjuvants comprise complex nano- or micro-particle formulations, such as oil-in-water emulsions. In order to characterize interactions and compatibility of oil-in-water emulsion adjuvants with protein antigens in vaccines, effective protein characterization methods that can accommodate potential interference from high concentrations of lipid-based particles are needed. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) is a standard protein characterization technique which is affected by the presence of adjuvants such as oil-in-water emulsions. In this article, we investigate variations in SDS-PAGE methods that result in a reduction of adjuvant-induced staining artifacts. We have investigated whether the SDS method or the adjuvant composition were the reason for these artifacts and succeeded in reducing the artifacts with a modified sample preparation and different staining procedures. The best results were obtained by using gold staining or silver staining instead of a Coomassie Blue staining procedure. Moreover, the replacement of the dilution buffer (20% SDS to disrupt emulsion) by alternative detergents such as Tween® 80 and Triton® X-100 removed adjuvant-induced streaking artifacts at the top of the gel. These methods may be useful for improving characterization approaches of antigen-adjuvant mixtures by SDS-PAGE.

  9. Biochemical Evaluation of Withania somnifera Root Powder on Adjuvant-Induced Arthritis in Rats

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    Mahaboobkhan Rasool

    2015-04-01

    Full Text Available The present investigation was carried out to evaluate the biochemical effect of Withania somnifera Linn. Solanaceae, commonly known as ashwagandha on adjuvant induced arthritic rats. Results were compared to Indomethacin, a non steroidal anti-inflammatory drug. Arthritis was induced by an intra dermal injection of Complete Freund’s Adjuvant (0.1 ml into the right hind paw of Wistar albino rats. Withania somnifera root powder (1000 mg/kg/day and Indomethacin (3 mg/kg/day were orally administered for 8 days (from 11th to 18th day after adjuvant injection. After the experimental period, all the animals were sacrificed and serum, liver and spleen samples were collected for further biochemical analysis. A significant increase in the activities of gluconeogenic enzymes, tissue marker enzymes, blood glucose level, WBC, platelet count, erythrocyte sedimentation rate, and acute phase proteins (hyaluronic acid, fibrinogen and ceruloplasmin was observed in adjuvant-induced arthritic rats, whereas the activities of glycolytic enzymes, body weight, levels of hemoglobin, RBC count, and packed cell volume were found to be decreased. These biochemical alterations observed in arthritic animals were ameliorated significantly after the administration of Withania somnifera root powder (1000 mg/kg/b.wt and Indomethacin (3 mg/kg/b.wt. Our results suggest that Withania somnifera root powder is capable of rectifying the above biochemical changes in adjuvant arthritis and it may prove to be useful in treating rheumatoid arthritis.

  10. A Controlled Study Using Acupuncture as an Adjuvant to Treat Chemotherpay-Induced Nausea and Vomiting

    National Research Council Canada - National Science Library

    Lao, Lixing

    2000-01-01

    ...) on nausea and vomiting induced by chemotherapy in breast cancer patients. The primary aim of this study is to evaluate the usefulness of HA as an adjuvant on N/v in chemotherapy patients who do not respond to conventional antiemetics...

  11. Oral mucosal lesions, microbial changes, and taste disturbances induced by adjuvant chemotherapy in breast cancer patients

    DEFF Research Database (Denmark)

    Jensen, Siri Beier; Mouridsen, Henning T.; Bergmann, Olav Jonas

    2008-01-01

    OBJECTIVE: The aim of the study was to examine oral mucosal lesions, microbial changes, and taste disturbances induced by adjuvant chemotherapy (CT) in breast cancer patients during and 1 year after treatment. STUDY DESIGN: Forty-five consecutive breast cancer patients, eligible for adjuvant CT...... with cyclophosphamide, epirubicin or methotrexate, and 5-fluorouracil were followed before, during, 6 months and 1 year after CT and were compared to a control group of 31 breast cancer patients not receiving adjuvant CT. RESULTS: During CT, oral mucosal lesions developed including erythema (n = 10, 22%) and ulceration...... (n = 7, 16%). Five patients (11%) were diagnosed with oral candidosis. Scores of dental bacterial plaque and gingival inflammation increased during CT and the oral microbial composition changed towards a more acidophilic flora. Taste disturbances were experienced by 84% (n = 38) of the patients...

  12. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld's syndrome) - An update.

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    Watad, A; Quaresma, M; Brown, S; Cohen Tervaert, J W; Rodríguez-Pint, I; Cervera, R; Perricone, C; Shoenfeld, Y

    2017-06-01

    Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) has been widely described in many studies conducted thus far. The syndrome incorporates five immune-mediated conditions, all associated with previous exposure to various agents such as vaccines, silicone implants and several others. The emergence of ASIA syndrome is associated with individual genetic predisposition, for instance those carrying HLA-DRB1*01 or HLA-DRB4 and results from exposure to external or endogenous factors triggering autoimmunity. Such factors have been demonstrated as able to induce autoimmunity in both animal models and humans via a variety of proposed mechanisms. In recent years, physicians have become more aware of the existence of ASIA syndrome and the relationship between adjuvants exposure and autoimmunity and more cases are being reported. Accordingly, we have created a registry that includes at present more than 300 ASIA syndrome cases that have been reported by different physicians worldwide, describing various autoimmune conditions induced by diverse adjuvants. In this review, we have summarized the updated literature on ASIA syndrome and the knowledge accumulated since 2013 in order to elucidate the association between the exposure to various adjuvant agents and its possible clinical manifestations. Furthermore, we especially referred to the relationship between ASIA syndrome and systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS).

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

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    Dool-Ri Oh

    2014-01-01

    Full Text Available 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.

  14. Esculetin reduces leukotriene B4 level in plasma of rats with adjuvant-induced arthritis

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    Przemysław Rzodkiewicz

    2016-10-01

    Full Text Available Objectives : Esculetin (6,7-dihydroxycoumarin is a natural coumarin with anti-oxidant, anti-inflammatory and anti-nociceptive activity. It acts as a potent inhibitor of lipoxygenases (5-LOX and 12-LOX and decreases the production of matrix metalloproteinases (MMP-1, MMP-3 and MMP-9. Because both inhibition of lipoxygenases and inhibition of matrix metalloproteinases are effective strategies in the treatment of rheumatoid arthritis, we investigated whether esculetin may be effective in adjuvant-induced arthritis in rats. Material and methods : The study was performed on male Lewis rats, in the adjuvant-induced arthritis model. Rats were divided into two groups: control (treated with 1% methylcellulose and experimental (treated with esculetin – 10 mg/kg ip.. The tested compound was administered for 5 consecutive days starting on the 21st day after induction of arthritis. Each group consisted of 7 animals. After 5 days of treatment, rats were anesthetized. The concentration of leukotriene B4 (LTB4 in plasma was determined by a competitive enzyme immunoassay. Results : The LTB4 level in plasma of rats with adjuvant-induced arthritis is increased in comparison to rats without inflammation (362 ±34 vs. 274 ±15 pg/ml, p < 0.01, respectively. Five-day treatment with esculetin in adjuvant-induced arthritis rats decreases the LTB4 level to a level comparable with rats without inflammation (284 ±23 pg/ml, p < 0.01. Conclusions : LTB4 is the most potent chemotactic agent influencing neutrophil migration into the joint. It is known that its level in serum of patients with active rheumatoid arthritis is increased and correlates with disease severity. Some other lipoxygenase inhibitors have already been tested as potential drug candidates in clinical and preclinical trials for rheumatoid arthritis (Zileuton, PF-4191834. Because esculetin decreases the LTB4 level in plasma of rats in adjuvant-induced arthritis, it may also be considered as an attractive

  15. The value of Autoimmune Syndrome Induced by Adjuvant (ASIA) - Shedding light on orphan diseases in autoimmunity.

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    Segal, Yahel; Dahan, Shani; Sharif, Kassem; Bragazzi, Nicola Luigi; Watad, Abdulla; Amital, Howard

    2018-05-01

    Autoimmune Syndrome Induced by Adjuvant (ASIA) is a definition aimed to describe the common etiological process at the root of five clinical entities sharing similar symptomatology: macrophagic myofasciitis syndrome (MMF), Gulf War Syndrome (GWS), sick building syndrome (SBS), siliconosis, and post vaccination autoimmune phenomena. ASIA illustrates the role of environmental immune stimulating agents, or adjuvants, in the instigation of complex autoimmune reactions among individuals bearing a genetic preponderance for autoimmunity. The value of ASIA lies first in the acknowledgment it provides for patients suffering from these as yet ill-defined medical conditions. Equally important is the spotlight it sheds for further research of these poorly understood conditions sharing a common pathogenesis. In this article we elaborate on the significance of ASIA, review the current evidence in support of the syndrome, and address recent reservations raised regarding its validity. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Inhibitory effects of andrographolide on activated macrophages and adjuvant-induced arthritis.

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    Gupta, Swati; Mishra, Kamla Prasad; Singh, Shashi Bala; Ganju, Lilly

    2018-04-01

    Andrographolide, a diterpenoid lactone obtained from plant Andrographis paniculata, is used in South Asian countries to relieve various inflammatory symptoms. To study the effects of this agent, the impact of andrographolide on production of inflammatory mediators were delineated in mouse peritoneal macrophages (PMϕ). Inflammatory mediators like nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin-6 and related molecular mechanisms of andrographolide-mediated inhibition of enzymes/transcription factors were studied. In addition, the in vivo anti-inflammatory activity of andrographolide was evaluated in an adjuvant-induced arthritis rat model. The results indicated that andrographolide clearly inhibited the production of NO and TNF-α in lipopolysaccharide-activated PMϕ in a dose-related manner. Immunoblot analyses revealed that andrographolide suppressed activation of both inducible NO synthase and cyclo-oxygenase-2 by directly targeting nuclear transcription factor (NF)-κB. Complete Freund's Adjuvant-induced paw edema in rats was also significantly inhibited by andrographolide treatment. From the data, we concluded that andrographolide imparted anti-inflammatory effects by suppressing two key inflammatory enzymes and a signaling pathway that mediates expression of variety of inflammatory cytokines/agents in situ. It is plausible that eventually, after further toxicologic characterization, andrographolide might be useful as a drug for the clinical treatment of various inflammatory diseases like rheumatoid arthritis or diseases associated with joint pain.

  17. Incidence of chemotherapy-induced amenorrhea in premenopausal women treated with adjuvant FOLFOX for colorectal cancer.

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    Cercek, Andrea; Siegel, Cara L; Capanu, Marinela; Reidy-Lagunes, Diane; Saltz, Leonard B

    2013-09-01

    Studies indicate that the incidence of young women diagnosed with colorectal cancer is rising, thus there is an increasing number of female colorectal cancer survivors of premenopausal and child-bearing age. Adjuvant FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy is the most widely used standard treatment for stage III and high-risk stage II colon cancer. We evaluated the incidence of FOLFOX-induced amenorrhea in women age 50 and younger treated with adjuvant therapy for colorectal cancer. A search of pharmacy records identified 119 women age 50 or younger who received adjuvant FOLFOX chemotherapy at Memorial Sloan-Kettering for stage II or III colorectal cancer from January 2002 and January 2011. Eligible patients were mailed an anonymous questionnaire. The returned surveys were reviewed and the results tallied. Seventy-three patients returned the questionnaire. Twenty-four patients were excluded from analysis: 19 were treated with pelvic radiotherapy, 2 patients had undergone bilateral oophorectomy, 2 had a hysterectomy, and 1 stopped menstruating before diagnosis. Forty-nine patient responses were analyzed. In total, 41% (n = 20) experienced amenorrhea during chemotherapy. Sixteen percent had persistent amenorrhea 1 year after completion of chemotherapy. The incidence of amenorrhea during chemotherapy trended higher in patients aged older than 40 compared with patients aged 40 and younger (59% vs. 31% [P = .075]). There was no statistically significant difference in persistent amenorrhea between the 2 age groups (24% vs. 13%; P = .42). In this retrospective series, there appears to be a trend toward FOLFOX induced amenorrhea during chemotherapy increasing with age. Twenty-four percent of women older than the age of 40 were found to have persistent amenorrhea after FOLFOX therapy. Because of the small sample size, the study is underpowered to detect a statistically significant difference between older and younger patients. Prospective studies

  18. The effect of adjuvants on the immune response induced by a DBL4e-ID4 VAR2CSA based Plasmodium falciparum vaccine against placental malaria

    DEFF Research Database (Denmark)

    Pinto, V V; Salanti, A; Joergensen, L M

    2012-01-01

    720, Alhydrogel(®) and CAF01. Antibodies induced against DBL4¿-ID4 in combination with these adjuvants inhibited parasite binding to CSA from 82% to 99%. Although, different epitope recognition patterns were obtained for the different formulations, all adjuvant combinations induced strong Th1 and Th2......¿-ID4 to induce binding-inhibitory antibodies when formulated with adjuvants approved for human use. We have characterized the immune response of DBL4¿-ID4 in combination with Freund's complete and incomplete adjuvant and with three adjuvants currently being used in clinical trials: Montanide(®) ISA...... type responses, resulting in IgG with similar binding strength, with to the DBL4¿-ID4 antigen. These results demonstrate that the DBL4¿-ID4 antigen is highly immunogenic and that binding inhibitory antibodies are induced when formulated with any of the tested adjuvants....

  19. Autoimmune Syndrome Induced by Adjuvants (ASIA after Silicone Breast Augmentation Surgery

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    Daniel Nunes e Silva, MD

    2017-09-01

    Full Text Available Summary:. Generally, the main complications of silicone implantation are local symptoms. However, some patients develop late-onset systemic symptoms often associated with a rare form of hyperactive immune response, as part of a syndrome known as autoimmune syndrome induced by adjuvants (ASIA. Reported cases of ASIA have shown resolution with explantation, but not with immunomodulatory therapy. In this report, we described a case of a previously healthy 23-year-old woman, who has undergone silicone breast implant augmentation, for aesthetic reasons, and developed localized cutaneous impairment 3 years postsurgery. She received a diagnosis of ASIA with a new presentation: Lupus-like manifestation through localized cutaneous impairment. This patient’s symptoms were managed without the need for surgical intervention, which has not been previously reported, because the patient did not want an explantation for aesthetic reasons. The patient was started on hydroxychloroquine, 400 mg per day, and remains asymptomatic after 2 years of treatment. The exact predisposition to ASIA is still unknown. Without implant explantation and with immunomodulatory treatment, this patient’s condition substantially improved. Based on our current understanding of this disease, it might not be prudent to indicate breast augmentation with silicone implants in patients with documented autoimmune reaction to an adjuvant, an established autoimmune condition, or genetic predisposition. However, if a patient does develop silicone-induced ASIA, explantation is no longer the only successfully reported option, as these symptoms can be managed with immune suppression.

  20. Relation cellular- molecular between serum IL10 levels and hyperalgesia variation in adjuvant- induced arthritis

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    Zenab Akhtari

    2015-01-01

    Full Text Available Background: Regarding to the important anti-inflammatory role of IL10 during inflammation process and hyperalgesia and edema variation during CFA-induced arthritis and also the increase of Spinal mu opioid receptor (mOR expression, in this study researchers investigate the role of serum IL10 level on mOR expression and edema and hyperalgesia variation during different stages of Complete Freund`s Adjuvant (CFA - induced arthritis in male Wistar rats. Materials and Methods: Mono-arthritis was induced by CFA and inflammatory symptoms (hyperalgesia and edema were assessed on 0, 3, 7, 14th and 21st days of study. Anti-IL10 was administered during the 21 days of study in different experimental groups. mOR expression were detected by western blotting on 0, 3,7, 14th and 21st days of study. Data was analyzed by SPSS statistical software version 19 with using one way ANOVA (post hoc Tokey's. Results: Our results showed that anti-IL10 administration in AA group (Adjuvant Arthritis caused an increase in the paw volume and hyperalgesia until 21st of study. Our study stated that there were no significant differences in spinal mOR expression between AA and AA+anti-IL10rats. Conclusion: Our study confirmed that anti-IL10administration caused to hyperalgesia and edema during AA inflammation. Also these findings suggested that mOR expression increased in chronic phase of AA inflammation, however an increase in the level of spinal mu opioid receptor (mOR expression during AA inflammation is not mediated directly via the effect of serum IL-10.

  1. Dural administration of inflammatory soup or Complete Freund's Adjuvant induces activation and inflammatory response in the rat trigeminal ganglion

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    Lukács, M; Haanes, K A; Majláth, Zs

    2015-01-01

    induces inflammatory activation in the trigeminal ganglion. METHODS: We performed topical administration of inflammatory soup (IS) or Complete Freund's Adjuvant (CFA) onto an exposed area of the rat dura mater in vivo for 20 min. The window was closed and the rats were sacrificed after 4 h and up to 7...

  2. Jatropha curcas leaves exert anti-arthritic activity on adjuvant-induced arthritis in rats

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    Hanif Nasiatul Baroroh

    2014-04-01

    Full Text Available BACKGROUND Jatropha curcas leaves have been proven to be anti-inflammatory and antioxidant. In this study we examined the antiarthritic effects of ethanolic extract of J. curcas leaves using adjuvant induced arthritis (AIA in rats. METHODS Male Wistar rats were divided into 6 groups (n=8, consisting of normal group (0.9% NaCl, control group (complete Freund’s adjuvant/CFA 1 mg/ml, sodium diclofenac group at a dose of 6.75 mg/kg (p.o, ethanolic extract of J.curcas groups at doses of 150 mg/kg (p.o, 300 mg/kg (p.o and 600 mg/kg (p.o. Each group was induced by 0.2 ml CFA on day 1 and a booster injection on day 5. Extracts of J. curcas were administered on days 14-28. Arthritic scores were determined, then analyzed using Kruskal Wallis followed by Mann Whitney tests. Mobility scores were analyzed using one way analysis of variance, followed by least significant difference multiple comparison test. Arthritic joint histopathology was observed on day 29. RESULTS The results showed that the ethanolic extract of J. curcas leaves at doses of 150 mg/kg, 300 mg/kg and 600 mg/kg significantly reduced arthritis scores (p<0.05 compared to control group (CFA. The J. curcas leaf extract at doses of 150 and 300 mg/kg BW decreased mobility scores. Histopathology studies showed that the J. curcas extract reduced edema and cartilage destruction in arthritic joints. CONCLUSIONS The J. curcas leaf extract had anti-arthritic effects by reducing arthritis scores and mobility scores. The extract should be further examined as a potential candidate for anti-arthritic therapies.

  3. Therapeutic effects of Hominis placenta herb-acupuncture in adjuvant-induced arthritis rat

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    MiJung Yeom

    2002-02-01

    Full Text Available Rheumatoid arthritis (RA is a chronic inflammatory autoimmune disease, characterized by leukocyte infiltration, a chronic inflammation of the joint, a pannus formation and the extensive destruction of the articular cartilage and bone. Several proinflammatory cytokines such as tumor necrosis factor-α (TNF-α, interleukin-1β (IL-1β and interleukin 6 (IL-6 have been implicated in the pathological mechanisms of synovial tissue proliferation, joint destruction and programmed cell death in rheumatoid joint. In the Korean traditional medicine, Hominis placenta (HP as an herbal solution of herb-acupuncture has been widely used to treat the inflammatory diseases including RA. In order to study the medicinal effect of HP herb-acupuncture on rheumatoid joint, an adjuvant-induced arthritis (AIA was generated by the injection of 1.5 mg of Mycobacterium tuberculosis, emulsified in squalene, to the base of the tail of Spraque-Dawley (SD rats. After onset stage of polyarthritis, HP was daily injected to the Zusanli (ST36 acupuncture points in both of rat lags and the expression patterns of cytokines such as TNF-α, IL-1β, and IL-6 at the knee joint were analyzed using immunostaining and RT-PCR. The HP herb-acupuncture was found to be effective to alleviate the arthritic symptoms in adjuvant-induced arthritic rats as regards the joint appearance and the expression profiles of inflammatory cytokines. In conclusion, therapeutic effects of HP herb-acupuncture on the rat with AIA might be related to anti-inflammatory activities of the hurb-acupuncture.

  4. Polyphenolics isolated from virgin coconut oil inhibits adjuvant induced arthritis in rats through antioxidant and anti-inflammatory action.

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    Vysakh, A; Ratheesh, M; Rajmohanan, T P; Pramod, C; Premlal, S; Girish kumar, B; Sibi, P I

    2014-05-01

    We evaluated the protective efficacy of the polyphenolic fraction from virgin coconut oil (PV) against adjuvant induced arthritic rats. Arthritis was induced by intradermal injection of complete Freund's adjuvant. The activities of inflammatory, antioxidant enzymes and lipid peroxidation were estimated. PV showed high percentage of edema inhibition at a dose of 80mg/kg on 21st day of adjuvant arthritis and is non toxic. The expression of inflammatory genes such as COX-2, iNOS, TNF-α and IL-6 and the concentration of thiobarbituric acid reactive substance were decreased by treatment with PV. Antioxidant enzymes were increased and on treatment with PV. The increased level of total WBC count and C-reactive protein in the arthritic animals was reduced in PV treated rats. Synovial cytology showed that inflammatory cells and reactive mesothelial cells were suppressed by PV. Histopathology of paw tissue showed less edema formation and cellular infiltration on supplementation with PV. Thus the results demonstrated the potential beneficiary effect of PV on adjuvant induced arthritis in rats and the mechanism behind this action is due to its antioxidant and anti-inflammatory effects. Copyright © 2014 Elsevier B.V. All rights reserved.

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

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    Shankar, J. [Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago (United States); Thippegowda, P.B., E-mail: btprabha@uic.edu [Department of Pharmacology, (M/C 868), College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612 (United States); Kanum, S.A. [Department of Chemistry, Yuvaraj' s College, University of Mysore, Mysore (India)

    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.

  6. Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

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    Zhang, Jing; Li, Pei; Guo, Hai-fang; Liu, Li; Liu, Xiao-dong

    2012-01-01

    Aim: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E2 (PGE2) as a biomarker. Methods: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE2 production in blood cells was investigated in vitro. Results: Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE2 in both normal and arthritic rats. The inhibitory effect on PGE2 levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid Imax model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production in vivo. The Imax model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE2 production in blood cells in vitro. Conclusion: Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid Imax can be used to fit the relationship between the plasma PGE2 and diclofenac levels in both normal rats and FCA-induced arthritic rats. PMID:22842736

  7. Comparing the Effect of Myristica fragrans and Flunixin on Adjuvant-Induced

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    Hossein Najafzadeh

    2014-02-01

    Full Text Available Background: Nutmeg, Myristica fragrans Houtt, has shown anti-inflammatory properties in some studies. At present experimental study, we evaluated the effect of seed extract of nutmeg on adjuvant-induced arthritis in rats in comparison with flunixin meglumine. Materials and Methods: Experimental study was done in six groups of Wistar rats (each group 8 rats as following: Group 1 was kept as control under similar conditions to other groups. All other rats received complete Freund's adjuvant at dose 0.1 ml which injected under skin of foot. Group 2 was received vehicle (normal saline. Group 3 received flunixin intraperitonealy at dose of 2 mg/kg body weight of rats daily for 12 days. Group4 to 6 received extract of nutmeg at dose 100, 200 and 300 mg/kg intraperitonealy and daily for 12 days. Four rats in each group were anesthetized and blood collected for serum analysis on 12th day. The ankle joint prepared for histopathological examination. The remained rats were kept until 21th day. Levels of the cytokine TNF-α in serum was measured using ELISA kit. Results: The serum levels of TNF-α in the group 2 were significantly increased; while nutmeg decreased the elevated TNF-α level in a dose-dependent manner but significantly with 300 mg/kg. The flunixin did not significantly decrease the levels of TNF-α. Nutmeg treated rats manifested pathological events in the ankle joints to a markedly lesser degree. Flunixin prevented pannus formation but it was ineffective in other lesions. Conclusion: Thus, nutmeg protected the joints against cartilage destruction and bone erosion in a dose-dependent manner.

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

    Science.gov (United States)

    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.

  9. The Potential Therapeutic Effect of Curcumin on the Adjuvant-induced Arthritis in Irradiated Rats

    International Nuclear Information System (INIS)

    El-Ghazaly, M.A.; Nada, A.S.; Hegazy, M.E.; Kenawy, S.A.

    2010-01-01

    Naturalistic that provide medical or health benefits, including prevention and treatment of diseases. They may be advantageous in inflammation and exposure to radiation. The study was conducted to investigate curcumin potential to modulate, counteract or prevent the inflammatory response induced in arthritic irradiated and non-irradiated rats using the adjuvant-induced arthritis model. Diclofenac was used as a reference standard non-steroidal anti-inflammatory drug (NSAID). Results indicated that exposure of rats to single dose of gamma-radiation (6 Gy) before induction of inflammation increased production of prostaglandin E2 (PGE2), tumour necrosis factor-gamma (TNF-gamma) and malondialdehyde (MDA) levels in serum. Blood glutathione (GSH) was shown to be reduced in irradiated animals. Curcumin suppressed the elevated levels of TNF-gamma, PGE2 and MDA and was able to restore blood GSH level. Reduction in liver contents of copper (Cu), zinc (Zn), selenium (Se) and iron (Fe) was recorded in animals irradiated before induction of inflammation. In addition, curcumin restored the hepatic contents of these trace elements. The present results suggest that irradiation of rats caused marked changes in the inflammatory response, while curcumin suppressed the inflammatory response in both irradiated and normal rats

  10. MicroRNA-124 inhibits the progression of adjuvant-induced arthritis in rats.

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    Nakamachi, Yuji; Ohnuma, Kenichiro; Uto, Kenichi; Noguchi, Yoriko; Saegusa, Jun; Kawano, Seiji

    2016-03-01

    MicroRNAs (miRNAs) are small endogenous, non-coding RNAs that act as post-transcriptional regulators. We analysed the in vivo effect of miRNA-124 (miR-124, the rat analogue of human miR-124a) on adjuvant-induced arthritis (AIA) in rats. AIA was induced in Lewis rats by injecting incomplete Freund's adjuvant with heat-killed Mycobacterium tuberculosis. Precursor (pre)-miR-124 was injected into the right hind ankle on day 9. Morphological changes in the ankle joint were assessed by micro-CT and histopathology. Cytokine expression was examined by western blotting and real-time RT-PCR. The effect of miR-124 on predicted target messenger RNAs (mRNAs) was examined by luciferase reporter assays. The effect of pre-miR-124 or pre-miR-124a on the differentiation of human osteoclasts was examined by tartrate-resistant acid phosphatase staining. We found that miR-124 suppressed AIA in rats, as demonstrated by decreased synoviocyte proliferation, leucocyte infiltration and cartilage or bone destruction. Osteoclast counts and expression level of receptor activator of the nuclear factor κB ligand (RANKL), integrin β1 (ITGB1) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) were reduced in AIA rats treated with pre-miR-124. Luciferase analysis showed that miR-124 directly targeted the 3'UTR of the rat NFATc1, ITGB1, specificity protein 1 and CCAAT/enhancer-binding protein α mRNAs. Pre-miR-124 also suppressed NFATc1 expression in RAW264.7 cells. Both miR-124 and miR-124a directly targeted the 3'-UTR of human NFATc1 mRNA, and both pre-miR-124 and pre-miR-124a suppressed the differentiation of human osteoclasts. We found that miR-124 ameliorated AIA by suppressing critical prerequisites for arthritis development, such as RANKL and NFATc1. Thus, miR-124a is a candidate for therapeutic use for human rheumatoid arthritis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  11. Electroacupuncture Inhibits Inflammation Reaction by Upregulating Vasoactive Intestinal Peptide in Rats with Adjuvant-Induced Arthritis

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    Tian-Feng He

    2011-01-01

    Full Text Available Acupuncture is emerging as an alternative therapy for rheumatoid arthritis (RA. However, the molecular mechanism underlying this beneficial effect of acupuncture has not been fully understood. Here, we demonstrated that electroacupuncture at acupoints Zusanli (ST36, Xuanzhong (GB39; and Shenshu (BL23 markedly decreased the paw swelling and the histologic scores of inflammation in the synovial tissue, and reduced the body weight loss in an adjuvant-induced arthritis rat model. However, the electrical stimulation at nonacupoint did not produce any beneficial effects against the experimental arthritis. Most interestingly, the electroacupuncture treatment resulted in an enhanced immunostaining for vasoactive intestinal peptide (VIP, a potent anti-inflammatory neuropeptide, in the synovial tissue. Moreover, the VIP-immunostaining intensity was significantly negatively correlated with the scores of inflammation in the synovial tissue (r=−0.483, P=.0026. In conclusion, these findings suggest that electroacupuncture may offer therapeutic benefits for the treatment of RA, at least partially through the induction of VIP expression.

  12. Neo-adjuvant chemotherapy with cisplatin induces low expression of NMDA receptors and postoperative cognitive impairment.

    Science.gov (United States)

    Cheng, Jing; Liu, Xiaoqing; Cao, Longhui; Zhang, Tianhua; Li, Huiting; Lin, Wenqian

    2017-01-10

    Whether Neo-adjuvant chemotherapy can affect patients' postoperative brain function is not clear. In this study, we investigated the effect of preoperative cisplatin treatment on postoperative cognitive function and its possible mechanism in rats. Moreover, we also tested whether the NMDAR inhibitor memantine could attenuate cisplatin-induced alterations. 12-month-oldSprague-Dawley rats randomly received an intraperitoneal injection of either cisplatin once a week at a dose of 3mg/kg for three consecutive weeks or an equivalent volume of normal saline. After the injections, the normal saline injection group was divided into 3 groups (n=5 each): a normal saline group (group S), normal saline+pentobarbital group (group SP), and normal saline+pentobarbital+operation group (group SPO).The cisplatin injection group was divided into 3 groups: a cisplatin group (group C), cisplatin+pentobarbital group (group CP), and cisplatin+pentobarbital+operation group (group CPO).Rats in the group SP, SPO,CP and CPO were anaesthetized with sodium pentobarbital and then the SPO and CPO groups underwent a simple laparotomy operation. The effects of memantine were tested through two additional groups of rats (cisplatin+memantine group (group CM) and cisplatin+pentobarbital+operation+memantine group (group CPOM)). A Morris water maze test was performed to evaluate the spatial learning and memory ability five days after anesthesia or operation. After the test, the hippocampi were removed for detection of the expression of NMDAR by western bloting. The relevant protein expression levels of PSD95 and ERK1/2 were detected by western blot analysis. Rats treated with cisplatin had a longer mean escape latency and spent a shorter amount of time in the target quadrant than did the normal saline injection rats. Furthermore, the protein expression levels of NMDA receptors, PSD95 and ERK1/2 were decreased in cisplatin group and memantine could up-regulate their expression. These results suggest

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

    International Nuclear Information System (INIS)

    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

  14. Curcumin loaded solid lipid nanoparticles ameliorate adjuvant-induced arthritis in rats.

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    Arora, R; Kuhad, A; Kaur, I P; Chopra, K

    2015-08-01

    Rheumatoid arthritis (RA), a chronic and systemic inflammation, results in destruction of joints and cartilages. Effectiveness of curcumin has been established in a wide variety of inflammatory disorders, but its utility as a therapeutic agent is limited by its poor absorption, rapid metabolism and fast systemic elimination. To apprehend these limitations, we propose to use highly bioavailable curcumin loaded solid lipid nanoparticles (C-SLNs) for the treatment of RA. In the present study, the protective effect of curcumin and its SLNs was evaluated in complete Freund's adjuvant (CFA)-induced arthritis in rats. Arthritic rats exhibited marked decrease in paw withdrawal threshold in Randall-Selitto and von Frey hair test along with decreased reaction time in hot plate. Arthritic rats also showed significant joint hyperalgesia, joint stiffness and increased paw volume along with marked decrease in mobility score. Arthritic rats showed a significant increase in blood leukocyte count, oxidative-nitrosative stress, tumour necrosis factor-α, C-reactive protein, cyclic citrullinated peptide antibody levels and radiological alterations in tibiotarsal joint. C-SLN administration (10 and 30 mg/kg), when compared with free curcumin (10 and 30 mg/kg), significantly and dose dependently ameliorated various symptoms of arthritis in rats, improved biochemical markers and preserved radiological alterations in joints of arthritic rats. The current findings suggest the protective potential of curcumin-SLNs in ameliorating CFA-induced arthritis in rats through attenuation of oxido-inflammatory and immunomodulatory cascade. Further, the results emphasize that SLNs are a novel approach to deliver curcumin into the inflamed joints and improve its biopharmaceutical performance. © 2014 European Pain Federation - EFIC®

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

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    Zheng ZL

    2015-08-01

    Full Text Available Zhaoling Zheng,1,* YanHua Sun,2,* Ziliang Liu,1 Mingqin Zhang,1 Chunqing Li,1 Hui Cai3 1Department of Traditional Chinese Medicine, Dongying People’s Hospital, Dongying, 2Shandong Provincial Key Laboratory of Microparticles Drug Delivery Technology, Jinan, 3Department of Integrated Traditional Chinese Medicine and Western Medicine, Nanjing Jinling Hospital, Nanjing, People’s Republic of China *These authors contributed equally to this work 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

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

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

    2015-01-01

    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. 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. 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 for the CM-Ns were more than

  18. Anti-hyperalgesic and anti-inflammatory effects of long termcalcium administrationduring adjuvant-induced arthritisin rats

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    Setareh Khashaee

    2015-12-01

    Full Text Available Introduction: Inflammation and edema Symptoms are physiological response to triggers that can be induced by different mediators such as cytokines. Rheumatoid arthritis is the most common form of arthritis which is characterized by chronic inflammation of the synovial membrane, severe and debilitating pain and progressive cartilage injury. It is clear that cytokines are involved in different stages of inflammation by inducing pro-inflammatory effects; TNF-α as a cytokine involved in the pathogenesis of rheumatoid arthritis. In this study we attempted to investigate the role of prescription of calcium to reduce inflammatory edema and serum TNF-α level during different stages of arthritic inflammation induced by Complete Freund Adjuvant (CFA injection in male Wistar rats.Methods:In this Applicable-Fundamental study, we used male Wistar rats and adjuvant arthritis was created by once subcutaneous injection of CFA in the right hindpaw of animals on day zero in experimental groups. Various doses of calcium were prepared and injected within 21 days of study. Hyperalgesia and paw volume changes wereassessed byradiant heat andplethysmometer over several days, respectively. The serum levels of TNF-α were studied by ELISA standard kit of rat during various phases and were measured according to the kit.Results:The results indicated dose related effects of long term calcium administration on edema, hyperalgesia and serum TNF-α level reduction. Daily treatment with effective dose of calcium (5 mg/kg in AA+ Ca group significantly decreased paw edema, hyperalgesia and serum TNF-α level incomparison to AA and AA+ Vehicle groups on days 7, 14 and 21 of study.Conclusions:Findings of this study showed;long term administration of calcium in the proper dosage can act as an anti-inflammatory agent and pain modulator during adjuvant-induced arthritis and a part of those effects may conducted by decreasing of serum TNF-α level.

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

    Science.gov (United States)

    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.

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

    International Nuclear Information System (INIS)

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

    2014-01-01

    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 ⁎ 02:01-restricted, cytotoxic T lymphocyte (CTL) epitope derived from influenza A virus. HLA-A ⁎ 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

  1. Effects of mesenchymal stem cells conditioned medium on behavioral aspects of inflammatory arthritic pain induced by CFA adjuvant

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    Vida Nazemian

    2016-07-01

    Full Text Available Background: Rheumatoid arthritis is a type of inflammatory pain and is an autoimmune and chronic inflammatory disease which can lead to hyperalgesia, edema and decreased motor activity in affected area. Mesenchymal stem cells conditioned medium (MSC-CM has anti-inflammatory mediators which can regulate the immune responses, alleviate inflammatory symptoms and has a paracrine effects too. The aim of this study was to evaluate the effects of mesenchymal stem cells conditioned medium on behavioral aspects of inflammatory arthritic pain which induced by CFA adjuvant.Materials and Methods: Complete Freund’s adjuvant (CFA-induced arthritis (AA was caused by single subcutaneous injection of CFA into the rats hind paw on day zero. MSC-CM was administered daily and intraperitoneal during the 21 days of the study after CFA injection. Hyperalgesia and edema were assessed on days 0, 7, 14 and 21 of the study respectively with radian heat and plethysmometer instrument.Results: The results of this study indicated the significant roles of MSC-CM in betterment of inflammatory symptoms such as hyperalgesia and edema during different stages of inflammation caused by CFA. The continuing injection of MSC-CM could reduce the inflammatory symptoms.Conclusion: Long term treatment by MSC-CM can alleviate hyperalgesia and edema and decrease those to the level of the time before induction of inflammation.   

  2. Low-dose X-irradiation of adjuvant-induced arthritis in rats. Efficacy of different fractionation schedules

    International Nuclear Information System (INIS)

    Liebmann, A.; Hindemith, M.; Jahns, J.; Kamprad, F.; Hildebrandt, G.; Madaj-Sterba, P.; Weisheit, S.

    2004-01-01

    Background and purpose: low-dose radiotherapy is widely accepted as a very effective treatment option for inflammatory symptoms associated with painful degenerative joint disorders. Radiation doses and fractionation schedules in practical use are empirical and mainly based on clinical observations. Experimental data are rare. The efficacy of low-dose X-irradiation on adjuvant induced arthritis in rats using different fractionation schemes was investigated in vivo, in order to explore whether there is a dose and fractionation dependence. Material and methods: adjuvant arthritis in female lewis rats (n = 128) was induced by intradermal injection of heat-inactivated Mycobacterium tuberculosis on day 0. Both arthritic hind paws were sham-irradiated (group 1: days 10-14; group 2: days 15-19; group 3: days 22-26) or X-irradiated with either 5 x 1.0 Gy (group 4: days 10-14; group 6: days 15-19; group 8: days 22-26; group 10: days 10, 12, 14, 16, and 18) or 5 x 0.5 Gy (group 5: days 10-14; group 7: days 15-19; group 9: days 22-26; group 11: days 10, 12, 14, 16, and 18; group 12: days 10-14 and 22-26). The clinical parameters arthritis score (AS), hind paw volume (HPV), and body weight were determined. Results: a significant decrease of the clinical arthritis parameters was observed following 5 x 0.5 Gy or 5 x 1.0 Gy during the acute maximum of the inflammatory response (days 15-19). The most pronounced treatment effect was reached after two daily fractionated series of 5 x 0.5 Gy with an early treatment onset (days 10-14) and repetition in interval (days 22-26). After the application of 5 x 1.0 Gy on days 10-14 or in a protracted scheme (days 10, 12, 14, 16, and 18), only a nonsignificant positive trend could be detected. Daily fractionated X-irradiation in the chronic phase of adjuvant arthritis (days 22-26) did not show any positive clinical effect. Conclusion: low-dose radiotherapy is able to prevent a full-blown arthritic reaction if given during the florid phase of

  3. Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

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    Marco Malavolta

    2018-01-01

    Full Text Available The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2 pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

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

    Science.gov (United States)

    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. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Involvement of chronic epipharyngitis in autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA).

    Science.gov (United States)

    Hotta, Osamu; Tanaka, Ayaki; Torigoe, Akira; Imai, Kazuaki; Ieiri, Norio

    2017-02-01

    The epipharynx is an immunologically active site even under normal conditions, and enhanced immunologic activation is prone to occur in response to an upper respiratory infection, air pollution, and possibly to vaccine adjuvants. Due to the potential link between the central nervous system and immune function, a relationship between epipharyngitis and autonomic nervous disturbance as well as autoimmune disease has been suggested. Various functional somatic symptoms have been described after human papillomavirus (HPV) vaccination, although a causal relationship has not been established. We examined the epipharynx in young women showing functional somatic symptoms following HPV vaccination. Surprisingly, despite having minimal symptoms involving the pharynx, all patients were found to have severe epipharyngitis. In addition, significant improvement in symptoms was seen in most patients who underwent epipharyngeal treatment. Thus, we speculate that the chronic epipharyngitis potentially caused by the vaccine adjuvant may be involved in the pathogenesis of functional somatic syndrome (FSS) post-HPV vaccination. Further, we suggest that epipharyngeal treatment may be effective for various types of FSS regardless of the initial cause, as well as for some autoimmune diseases, and that this may be an important direction in future research.

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

    Science.gov (United States)

    McCarson, Kenneth E

    2015-09-01

    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). Copyright © 2015 John Wiley & Sons, Inc.

  7. Immunizations with hepatitis B viral antigens and a TLR7/8 agonist adjuvant induce antigen-specific immune responses in HBV-transgenic mice

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    Ying Wang

    2014-12-01

    Conclusions: Immunization with CL097-conjugated HBV-Ag reversed immune tolerance in HBV-Tg mice and induced antigen-specific immune responses. TLR7/8 agonists appear to be potent adjuvants for the induction of antigen-specific Th1 responses in an immune tolerant state.

  8. Anti-arthritic activity of Xanthium strumarium L. extract on complete Freund׳s adjuvant induced arthritis in rats.

    Science.gov (United States)

    Lin, Bing; Zhao, Yong; Han, Ping; Yue, Wei; Ma, Xue-Qin; Rahman, Khalid; Zheng, Cheng-Jian; Qin, Lu-Ping; Han, Ting

    2014-08-08

    Xanthium strumarium L. fruit (Xanthiu fruit) has been traditionally used as a medicinal herb in China for the treatment of many ailments including rheumatoid arthritis. However, the anti-arthritic activity of Xanthium strumarium fruit has still not been demonstrated. In the present study, we confirmed that the extract of Xanthium strumarium (EXS) prevents rheumatoid arthritis induced by Complete Freund׳s Adjuvant (CFA) in rats. Male Wistar rats (160±10 g) were immunized by intradermal injection of 0.1 mL of CFA into the left hind metatarsal footpad. EXS was administered orally at a dose of 300 and 75 mg/kg once a day after the induction of adjuvant arthritis. Methotrexate (3 mg/kg, twice a week) was used as a positive control. Paw swelling, arthritic score, body weight loss, spleen index, thymus index, serum cytokines, inflammatory mediators and histological change were measured. The chemical profile of EXS was analyzed by HPLC-DAD. We found that the EXS significantly suppressed paw swelling and arthritic score, increased body weight loss and decreased the thymus index. The overproduction of TNF-α and IL-1β were remarkably suppressed in the serum of all EXS-treated rats, and in contrast IL-10 was markedly increased. The level of COX-2 and 5-LOX was also decreased with EXS treatment. Ten phenolic acid derivatives were identified from 14 detected peaks by HPLC-DAD with the reference substances and verified by LC-MS. These results suggest the potential effect of EXS as an anti-arthritis agent towards CFA-induced arthritis in rats. Xanthium strumarium has the potential to be regarded as a candidate for use in general therapeutics and as an immune-modulatory medicine in rheumatoid arthritis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Effects of Trichilia monadelpha (Meliaceae extracts on bone histomorphology in complete Freund’s adjuvant-induced arthritis

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    INEMESIT OKON BEN

    2017-06-01

    Full Text Available Aim: To assess the effect of petroleum ether extract (PEE, ethyl acetate extract (EthE, and ethanol extract (EAE of Trichilia monadelpha stem bark on bone histomorphology in arthritis. Methods: Percentage inhibition of edema and arthritic scores in complete Freund’s adjuvant-induced (0.1 ml of 5 mgml-1 of heat killed Mycobacterium tuberculosis in paraffin oil injected sub-plantar into the right hind paw arthritic Sprague-Dawley rats treated with PEE, EthE, or EAE (10, 30, and 100 mgkg-1, dexamethasone (0.3-3.0 mgkg-1 or methotrexate (0.1–1.0 mgkg-1 over a 28-day period were estimated. Rat paws were radiographed and scored. Body weights were taken and paw tissues harvested for histopathological studies. Results: The extracts significantly (P≤0.01-0.0001 and dose-dependently reduced the polyarthritic phase of arthritis. EAE and PEE significantly (P≤0.01-0.0001 minimized edema spread from acute arthritic phase (day 0-10 to polyarthritic phase (day 10-28. EthE improved deteriorated body weight in arthritis. All extracts significantly (P≤0.05-0.01 improved arthritic score; reducing erythema, swelling and joint rigidity, and also significantly (P≤0.05-0.01 reduced hyperplasia, pannus formation, and exudation of inflammatory cells into synovial spaces. Conclusion: The stem bark extracts of Trichilia monadelpha reduce bone tissue damage and resorption associated with adjuvant-induced arthritis, hence could be useful in managing arthritis in humans. [J Complement Med Res 2017; 6(2.000: 177-185

  10. A Schistosoma japonicum chimeric protein with a novel adjuvant induced a polarized Th1 immune response and protection against liver egg burdens

    Directory of Open Access Journals (Sweden)

    Xue Xiangyang

    2009-05-01

    Full Text Available Abstract Background Schitosomiasis japonica is still a significant public health problem in China. A protective vaccine for human or animal use represents an important strategy for long-term control of this disease. Due to the complex life cycle of schistosomes, different vaccine design approaches may be necessary, including polyvalent subunit vaccines. In this study, we constructed four chimeric proteins (designated SjGP-1~4 via fusion of Sj26GST and four individual paramyosin fragments. We tested these four proteins as vaccine candidates, and investigated the effect of deviating immune response on protection roles in mice. Methods The immunogencity and protection efficacy of chimeric proteins were evaluated in mice. Next, the chimeric protein SjGP-3 was selected and formulated in various adjuvants, including CFA, ISA 206, IMS 1312 and ISA 70M. The titers of antigen-specific IgG, IgE and IgG subclass were measured. The effect of adjuvant on cytokine production and percentages of CD3+CD8-IFN-γ+ cells and CD3+CD8-IL-4+ cells were analyzed at different time points. Worm burdens and liver egg counts in different adjuvant groups were counted to evaluate the protection efficacy against cercarial challenge. Results Immunization of mice with chimeric proteins provided various levels of protection. Among the four proteins, SjGP-3 induced the highest level of protection, and showed enhanced protective efficacy compared with its individual component Sj26GST. Because of this, SjGP-3 was further formulated in various adjuvants to investigate the effect of adjuvant on immune deviation. The results revealed that SjGP-3 formulated in veterinary adjuvant ISA 70M induced a lasting polarized Th1 immune response, whereas the other adjuvants, including CFA, ISA 206 and IMS 1312, generated a moderate mixed Th1/Th2 response after immunization but all except for IMS 1312 shifted to Th2 response after onset of eggs. More importantly, the SjGP-3/70M formulation induced

  11. Jobelyn® attenuates inflammatory responses and neurobehavioural deficits associated with complete Freund-adjuvant-induced arthritis in mice.

    Science.gov (United States)

    Omorogbe, Osarume; Ajayi, Abayomi M; Ben-Azu, Benneth; Oghwere, Ejiroghene E; Adebesin, Adaeze; Aderibigbe, Adegbuyi O; Okubena, Olajuwon; Umukoro, Solomon

    2018-02-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects the physical and psychosocial wellbeing of the patients and a major cause of work disability. Current drugs for its treatment only provide palliative effect, as cure for the disease still remains elusive. Jobelyn ® (JB), a potent anti-oxidant and anti-inflammatory dietary supplement obtained from Sorghum bicolor, has been claimed to relieve arthritic pain. Thus, this study was designed to evaluate its effect on inflammatory and biochemical changes as well as neurobehavioural deficits associated with complete Freund-adjuvant (CFA)-induced arthritis in mice. The effect of JB (50, 100 and 200 mg/kg) on inflammatory oedema, neurobehavioural deficits, levels of biomarkers of oxidative stress and inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) induced by 0.1 mL of CFA (10 mg/mL) was evaluated in male Swiss mice. Oral administration of JB (100 and 200 mg/kg) reduced inflammatory paw volume and reversed sensorimotor deficits induced by CFA. JB also reduced pain episodes, anxiety and depressive-like symptoms in CFA-mice. The increased level of oxidative stress in the joint and brain tissues of CFA-mice was reduced by JB. It also decreased tumor necrosis factor-alpha and interleukin-6 levels induced by CFA in the joint tissue of mice. These findings suggest that Jobelyn ® attenuates inflammatory responses induced by CFA in mice via inhibition of oxidative stress and release of inflammatory cytokines. The ability of JB to attenuate CFA-induced nociception, sensorimotor deficits and depressive-like symptom suggests it might improve the quality of life of patients with arthritic conditions. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Oral and nasal administration of chicken type II collagen suppresses adjuvant arthritis in rats with intestinal lesions induced by meloxicam.

    Science.gov (United States)

    Zheng, Yong-Qiu; Wei, Wei; Shen, Yu-Xian; Dai, Min; Liu, Li-Hua

    2004-11-01

    To investigate the curative effects of oral and nasal administration of chicken type II collagen (CII) on adjuvant arthritis (AA) in rats with meloxicam-induced intestinal lesions. AA model in Sprague-Dawley (SD) rats with or without intestinal lesions induced by meloxicam was established and those rats were divided randomly into six groups which included AA model, AA model+meloxicam, AA model+oral CII, AA model+nasal CII, AA model+ meloxicam+oral C II and AA model+meloxicam+nasal CII (n = 12). Rats was treated with meloxicam intragastrically for 7 d from d 14 after immunization with complete Freund's adjuvant (CFA), and then treated with chicken CII intragastrically or nasally for 7 d. Histological changes of right hind knees were examined. Hind paw secondary swelling and intestinal lesions were evaluated. Synoviocyte proliferation was measured by 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) method. Activities of myeloperoxidase (MPO) and diamine oxidase (DAO) from supernatants of intestinal homogenates were assayed by spectrophotometric analysis. Intragastrical administration of meloxicam (1.5 mg/kg) induced multiple intestinal lesions in AA rats. There was a significant decrease of intestinal DAO activities in AA+meloxicam group (P<0.01) and AA model group (P<0.01) compared with normal group. DAO activities of intestinal homogenates in AA+meloxicam group were significantly less than those in AA rats (P<0.01). There was a significant increase of intestinal MPO activities in AA+meloxicam group compared with normal control (P<0.01). Oral or nasal administration of CII (20 microg/kg) could suppress the secondary hind paw swelling(P<0.05 for oral CII; P<0.01 for nasal CII), synoviocyte proliferation (P<0.01) and histopathological degradation in AA rats, but they had no significant effects on DAO and MPO changes. However, oral administration of CII (20 microg/kg) showed the limited efficacy on arthritis in AA+meloxicam model and the

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

    Energy Technology Data Exchange (ETDEWEB)

    Kawano, Masaaki [Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Morikawa, Katsuma [Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501 (Japan); Suda, Tatsuya [Department of Microbiology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Laboratory for Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan); Ohno, Naohito [Laboratory for Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan); Matsushita, Sho [Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Allergy Center, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Akatsuka, Toshitaka [Department of Microbiology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan); Handa, Hiroshi, E-mail: handa.h.aa@m.titech.ac.jp [Solutions Research Laboratory, Tokyo Institute of Technology, Midori-ku, Yokohama 226-8503 (Japan); Matsui, Masanori, E-mail: mmatsui@saitama-med.ac.jp [Department of Microbiology, Faculty of Medicine, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495 (Japan)

    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.

  14. Vaccines, adjuvants and autoimmunity.

    Science.gov (United States)

    Guimarães, Luísa Eça; Baker, Britain; Perricone, Carlo; Shoenfeld, Yehuda

    2015-10-01

    Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Oral Administration of Shark Type II Collagen Suppresses Complete Freund’s Adjuvant-Induced Rheumatoid Arthritis in Rats

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    Wenhui Wu

    2012-03-01

    Full Text Available Objective: Shark type II collagen (SCII is extracted as a glycoprotein from the cartilage of blue shark (Prionace glauca. We aim to confirm the effects of oral tolerance of SCII on inflammatory and immune responses to the ankle joint of rheumatoid-arthritis rats induced by Complete Freund’s Adjuvant (CFA. Materials and Methods: The onset of rheumatoid arthritis (RA was observed 14 ± x days after injection of CFA. Rats in the control group were treated with acetic acid by oral administration (0.05 mmol kg−1d−1, days 14–28, while rats in experimental groups were treated by oral administration with SCII (1 or 3 mg kg−1d−1, days 14–28, Tripterygium wilfordii polyglycosidium (TWP (10 mg kg−1d−1, days 14–28, and bovine type II collagen from US (US-CII (1 mg kg−1d−1, days 14–28, respectively. The severity of arthritis was evaluated by the articular swelling. The immunological indexes observed included delayed type hypersensitivity (DTH reaction, the level of interleukins 10 (IL-10 in rat blood serum and morphological characterization. Mixed lymphocyte culture (MLC was performed to investigate the relationship between T cell apoptosis and specific immune tolerance induced by SCII. Results: Treatment with SCII for 2 weeks significantly attenuated the acute inflammation. The rats orally administrated with SCII at the level of 3 mg kg−1d−1 (SCII 3 and US-CII had decreased DTH reaction compared with rats in control group. Rats treated with SCII 3 had the highest level of IL-10 with 102 pg/mL. SCII with concentration of 10 μg/L could help to significantly enhance level of Fas/Apo-1 in T cell in vitro. The result of histological staining indicated that the recovery of the articular membranes of ankle joint in SCII 3 group was greatly enhanced. Conclusions: Our results suggest that appropriate dose of SCII can not only ameliorate symptoms but also modify the disease process of Complete-Freunds-Adjuvant-induced arthritis. Oral

  16. Anti-inflammatory and anti-oxidant properties of Sida rhombifolia stems and roots in adjuvant induced arthritic rats.

    Science.gov (United States)

    Narendhirakannan, R T; Limmy, T P

    2012-04-01

    Free radical stress leads to tissue injury and progression of disease conditions such as arthritis, hemorrhagic shock, atherosclerosis, diabetes, hepatic injury, aging and ischemia, reperfusion injury of many tissues, gastritis, tumor promotion, neurodegenerative diseases and carcinogenesis. Safer anti-oxidants suitable for long term use are needed to prevent or stop the progression of free radical mediated disorders. Herbal medicine provides a foundation for various traditional medicine systems worldwide. The Sida species is one of the most important families of medicinal plants in India. Hence, the present study was aimed to investigate the possible anti-oxidant potential of Sida rhombifolia extracts for 30 days on adjuvant induced arthritis in experimental rats. The altered levels of hematological parameters were reverted to near normal levels, especially the elevated rate of erythrocyte sedimentation was significantly reduced by S. rhombifolia extracts in experimental rats. Oral administration of root and stem of S. rhombifolia extracts significantly increased the levels of thiobarbituric acid reactive substances and activities of catalase and 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 and transmission electron microscopy observations made on the hind limb tissue.

  17. Curcumin potentiates the anti-arthritic effect of prednisolone in Freund's complete adjuvant-induced arthritic rats.

    Science.gov (United States)

    Kuncha, Madhusudana; Naidu, Vegi Ganga Modi; Sahu, Bidya Dhar; Gadepalli, Shankar Ganesh; Sistla, Ramakrishna

    2014-01-01

    The present study was aimed at investigating the effect of curcumin in combination with prednisolone for the effective treatment of arthritis with reduced side effects when glucocorticoids therapy is indicated. Arthritis was induced in wistar rats by subplantar injection of Freund's complete adjuvant, and animals were observed for the symptoms of arthritis during the period of 21 days. Combined treatment of curcumin with various doses of prednisolone (1.25, 2.5 and 5 mg/kg) was evaluated in order to ascertain the efficacy and toxicity induced by steroid. Arthritic animals showed significant increase in tumour necrosis factor-α and IL-1β levels in paw tissue and IL-1β in serum. Combined therapy of curcumin with low doses of prednisolone showed pronounced beneficial effect on joint swelling, leucocyte count and biochemical parameters compared with prednisolone groups. Among the different doses used in the study, prednisolone at 1.25 mg/kg in combination with curcumin showed beneficial anti-arthritic activity and also reduced the steroid toxicity. This is evidenced by increase in body weight, low toxicity to immune organs, reduction in leucocyte count, increase in spleen anti-oxidant enzymes and potent inhibition of cytokines in combination group. Therefore, combined treatment of curcumin with low doses of prednisolone may find therapeutic use in arthritis. © 2013 Royal Pharmaceutical Society.

  18. Suppressive effects of QFGJS, a preparation from an anti-arthritic herbal formula, on rat experimental adjuvant-induced arthritis

    International Nuclear Information System (INIS)

    Cai Xiong; Zhou Hua; Wong Yuenfan; Xie Ying; Liu Zhong Qiu; Jiang Zhhong; Bian Zhaoxiang; Xu Hongxi; Liu Liang

    2005-01-01

    To analyze the anti-arthritic effects of QFGJS (a pharmaceutical preparation from herbs) on rheumatoid arthritis, adjuvant-induced arthritis (AIA) was established in male SD rats, and two administration protocols, i.e., oral treatment with different doses of QFGJS on the day of arthritis induction or on the day when visible clinical signs of arthritis occurred, were initiated and continued until day 30. Treatments with QFGJS using both administration protocols significantly suppressed the incidence and severity of arthritis in a dose-dependent manner, showing dramatic reduction of paw swelling and ESR throughout the disease progression of AIA. Radiological and histopathological examinations showed markedly decreased tissue and bone destruction of ankle joints in the QFGJS-treated rats. The serum levels of TNF-α, IL-1β, and IL-6 were significantly decreased in the QFGJS-treated rats. QFGJS demonstrates pronounced anti-arthritic effects on AIA, indicating that this herbal preparation would be a potent candidate as a novel botanical drug for further investigation

  19. Adjuvant potential of virgin coconut oil extract on antiretroviral therapy-induced testicular toxicity: An ultrastructural study.

    Science.gov (United States)

    Ogedengbe, O O; Jegede, A I; Onanuga, I O; Offor, U; Peter, A I; Akang, E N; Naidu, E C S; Azu, O O

    2018-04-01

    The effects of Virgin coconut oil as an adjuvant to highly active antiretroviral therapy (HAART) were investigated on the testicular ultrastructure and biochemical markers in rats. Twenty male Sprague-Dawley rats, weighing 153-169 g were divided into four groups and treated as follows: control A (distilled water), B (HAART), C (HAART+Virgin coconut oil 10 ml/kg) and D (Virgin coconut oil [VCO] 10 ml/kg). Testicular segments were evaluated using transmission electron microscopy. Serum was assayed for testosterone, luteinising hormone, follicle stimulating hormone and testicular tissue for malondialdehyde and glutathione. Ultrastructure of basement membrane (Bm), mitochondria and spermatocytes was normal in the control group. HAART-treated group showed significant increase (p group. Mitochondrial cristae appear collapsed, and Sertoli cells showed cytoplasmic vacuolations. HAART+VCO group showed improved ultrastructural details in Bm, and Sertoli cell and Leydig cells show abundant lipid droplets. Virgin coconut oil-treated group showed thinning of Bm with otherwise normal ultrastructural features of organelles. HAART-treated group showed significant increase (p Virgin coconut oil improved testicular morphology and reversed HAART-induced ultrastructural alterations. Further studies on putative mechanism are required. © 2017 Blackwell Verlag GmbH.

  20. Local cryotherapy improves adjuvant-induced arthritis through down-regulation of IL-6 / IL-17 pathway but independently of TNFα.

    Science.gov (United States)

    Guillot, Xavier; Martin, Hélène; Seguin-Py, Stéphanie; Maguin-Gaté, Katy; Moretto, Johnny; Totoson, Perle; Wendling, Daniel; Demougeot, Céline; Tordi, Nicolas

    2017-01-01

    Local cryotherapy is widely and empirically used in the adjuvant setting in rheumatoid arthritis treatment, however its own therapeutic and anti-inflammatory effects are poorly characterized. We aimed to evaluate the effects of local cryotherapy on local and systemic inflammation in Adjuvant-induced arthritis, a murine model of rheumatoid arthritis. The effects of mild hypothermia (30°C for 2 hours) on cytokine protein levels (Multiplex/ELISA) were evaluated in vitro in cultured rat adjuvant-induced arthritis patellae. In vivo, local cryotherapy was applied twice a day for 14 days in arthritic rats (ice: n = 10, cold gas: n = 9, non-treated: n = 10). At day 24 after the induction of arthritis, cytokine expression levels were measured in grinded hind paws (Q-RT-PCR) and in the plasma (Multiplex/ELISA). In vitro, punctual mild hypothermia down-regulated IL-6 protein expression. In vivo, ice showed a better efficacy profile on the arthritis score and joint swelling and was better tolerated, while cold gas induced a biphasic response profile with initial, transient arthritis worsening. Local cryotherapy also exerted local and systemic anti-inflammatory effects, both at the gene and the protein levels: IL-6, IL-17A and IL-1β gene expression levels were significantly down-regulated in hind paws. Both techniques decreased plasma IL-17A while ice decreased plasma IL-6 protein levels. By contrast, we observed no effect on local/systemic TNF-α pathway. We demonstrated for the first time that sub-chronically applied local cryotherapy (ice and cold gas) is an effective and well-tolerated treatment in adjuvant-induced arthritis. Furthermore, we provided novel insights into the cytokine pathways involved in Local cryotherapy's local and systemic anti-inflammatory effects, which were mainly IL-6/IL-17A-driven and TNF-α independent in this model.

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

    Science.gov (United States)

    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...

  2. Attenuation of adjuvant-induced arthritis in rats by phonophoresis with an aqueous gel of the Amazonian plant Elaeoluma nuda (Sapotaceae).

    Science.gov (United States)

    Merini, Lilian Regiani; Furtado, Silvânia da Conceição; de Oliveira, Marcelo Miguel Brito; Carneiro, Ana Lúcia Basílio; Boechat, Antonio Luiz; Barcellos, José Fernando Marques

    2014-02-01

    Various species of the genus Pouteria (Elaeoluma) are used by the native population of Brazil because of, among other factors, their anti-inflammatory properties. The anti-inflammatory properties of the extract of the Amazonian plant Elaeoluma nuda were recently identified in prospective pharmacological studies. The objective of this study was to assess the anti-inflammatory effect of phonophoresis with aqueous gel extract of E. nuda in rat adjuvant-induced arthritis. Arthritis was induced in Lewis rats with an adjuvant. Phonophoresis with E. nuda gel was then administered daily and the results compared with those obtained with phonophoresis of diclofenac diethylammonium gel and ultrasound therapy without phonophoresis. Arthritis in the different groups was evaluated by plethysmometry. Proinflammatory cytokines TNF-α and IL-1α were quantified by cytometric bead array (CBA). The effect of phonophoresis of aqueous gel with E. nuda extract on arthritis in rats' paws (a 33% reduction compared with the controls) was the same as that produced by phonophoresis with diclofenac diethylammonium. Ultrasound therapy without phonophoresis produced no significant effect on the 21st day of therapy. There was a significant reduction in TNF-α and IL-1α levels in the group treated with phonophoresis with E. nuda gel (p=0.0042; p=0.0003, respectively). Our results demonstrate the anti-inflammatory effect of phonophoresis with E. nuda gel on cytokines TNF-α, IL-1α and adjuvant-induced arthritis. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines

    Science.gov (United States)

    Gasper, David J.; Neldner, Brandon; Plisch, Erin H.; Rustom, Hani; Imai, Hirotaka; Kawaoka, Yoshihiro; Suresh, M.

    2016-01-01

    CD8+ cytotoxic T lymphocytes (CTLs) are critical for clearing many viral infections, and protective CTL memory can be induced by vaccination with attenuated viruses and vectors. Non-replicating vaccines are typically potentiated by the addition of adjuvants that enhance humoral responses, however few are capable of generating CTL responses. Adjuplex is a carbomer-lecithin-based adjuvant demonstrated to elicit robust humoral immunity to non-replicating antigens. We report that mice immunized with non-replicating Adjuplex-adjuvanted vaccines generated robust antigen-specific CTL responses. Vaccination by the subcutaneous or the intranasal route stimulated systemic and mucosal CTL memory respectively. However, only CTL memory induced by intranasal vaccination was protective against influenza viral challenge, and correlated with an enhancement of memory CTLs in the airways and CD103+ CD69+ CXCR3+ resident memory-like CTLs in the lungs. Mechanistically, Myd88-deficient mice mounted primary CTL responses to Adjuplex vaccines that were similar in magnitude to wild-type mice, but exhibited altered differentiation of effector cell subsets. Immune potentiating effects of Adjuplex entailed alterations in the frequency of antigen-presenting-cell subsets in vaccine draining lymph nodes, and in the lungs and airways following intranasal vaccination. Further, Adjuplex enhanced the ability of dendritic cells to promote antigen-induced proliferation of naïve CD8 T cells by modulating antigen uptake, its intracellular localization, and rate of processing. Taken together, we have identified an adjuvant that elicits both systemic and mucosal CTL memory to non-replicating antigens, and engenders protective CTL-based heterosubtypic immunity to influenza A virus in the respiratory tract. Further, findings presented in this manuscript have provided key insights into the mechanisms and factors that govern the induction and programming of systemic and protective memory CTLs in the

  4. The CD8⁺ T Cell-Mediated Immunity Induced by HPV-E6 Uploaded in Engineered Exosomes Is Improved by ISCOMATRIXTM Adjuvant.

    Science.gov (United States)

    Manfredi, Francesco; di Bonito, Paola; Ridolfi, Barbara; Anticoli, Simona; Arenaccio, Claudia; Chiozzini, Chiara; Baz Morelli, Adriana; Federico, Maurizio

    2016-11-09

    We recently described the induction of an efficient CD8⁺ T cell-mediated immune response against a tumor-associated antigen (TAA) uploaded in engineered exosomes used as an immunogen delivery tool. This immune response cleared tumor cells inoculated after immunization, and controlled the growth of tumors implanted before immunization. We looked for new protocols aimed at increasing the CD8⁺ T cell specific response to the antigen uploaded in engineered exosomes, assuming that an optimized CD8⁺ T cell immune response would correlate with a more effective depletion of tumor cells in the therapeutic setting. By considering HPV-E6 as a model of TAA, we found that the in vitro co-administration of engineered exosomes and ISCOMATRIX TM adjuvant, i.e., an adjuvant composed of purified ISCOPREP TM saponin, cholesterol, and phospholipids, led to a stronger antigen cross-presentation in both B- lymphoblastoid cell lines ( and monocyte-derived immature dendritic cells compared with that induced by the exosomes alone. Consistently, the co-inoculation in mice of ISCOMATRIX TM adjuvant and engineered exosomes induced a significant increase of TAA-specific CD8⁺ T cells compared to mice immunized with the exosomes alone. This result holds promise for effective usage of exosomes as well as alternative nanovesicles in anti-tumor therapeutic approaches.

  5. The CD8+ T Cell-Mediated Immunity Induced by HPV-E6 Uploaded in Engineered Exosomes Is Improved by ISCOMATRIXTM Adjuvant

    Science.gov (United States)

    Manfredi, Francesco; di Bonito, Paola; Ridolfi, Barbara; Anticoli, Simona; Arenaccio, Claudia; Chiozzini, Chiara; Baz Morelli, Adriana; Federico, Maurizio

    2016-01-01

    We recently described the induction of an efficient CD8+ T cell-mediated immune response against a tumor-associated antigen (TAA) uploaded in engineered exosomes used as an immunogen delivery tool. This immune response cleared tumor cells inoculated after immunization, and controlled the growth of tumors implanted before immunization. We looked for new protocols aimed at increasing the CD8+ T cell specific response to the antigen uploaded in engineered exosomes, assuming that an optimized CD8+ T cell immune response would correlate with a more effective depletion of tumor cells in the therapeutic setting. By considering HPV-E6 as a model of TAA, we found that the in vitro co-administration of engineered exosomes and ISCOMATRIXTM adjuvant, i.e., an adjuvant composed of purified ISCOPREPTM saponin, cholesterol, and phospholipids, led to a stronger antigen cross-presentation in both B- lymphoblastoid cell lines ( and monocyte-derived immature dendritic cells compared with that induced by the exosomes alone. Consistently, the co-inoculation in mice of ISCOMATRIXTM adjuvant and engineered exosomes induced a significant increase of TAA-specific CD8+ T cells compared to mice immunized with the exosomes alone. This result holds promise for effective usage of exosomes as well as alternative nanovesicles in anti-tumor therapeutic approaches. PMID:27834857

  6. The Mincle-activating adjuvant TDB induces MyD88-dependent Th1 and Th17 responses through IL-1R signaling.

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    Christiane Desel

    Full Text Available Successful vaccination against intracellular pathogens requires the generation of cellular immune responses. Trehalose-6,6-dibehenate (TDB, the synthetic analog of the mycobacterial cord factor trehalose-6,6-dimycolate (TDM, is a potent adjuvant inducing strong Th1 and Th17 immune responses. We previously identified the C-type lectin Mincle as receptor for these glycolipids that triggers the FcRγ-Syk-Card9 pathway for APC activation and adjuvanticity. Interestingly, in vivo data revealed that the adjuvant effect was not solely Mincle-dependent but also required MyD88. Therefore, we dissected which MyD88-dependent pathways are essential for successful immunization with a tuberculosis subunit vaccine. We show here that antigen-specific Th1/Th17 immune responses required IL-1 receptor-mediated signals independent of IL-18 and IL-33-signaling. ASC-deficient mice had impaired IL-17 but intact IFNγ responses, indicating partial independence of TDB adjuvanticity from inflammasome activation. Our data suggest that the glycolipid adjuvant TDB triggers Mincle-dependent IL-1 production to induce MyD88-dependent Th1/Th17 responses in vivo.

  7. Anti-inflammatory effects and hepatotoxicity of Tripterygium-loaded solid lipid nanoparticles on adjuvant-induced arthritis in rats.

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    Xue, Mei; Jiang, Zhen-zhou; Wu, Tao; Li, Ji; Zhang, Liang; Zhao, Yan; Li, Xue-jun; Zhang, Lu-Yong; Yang, Shu-yu

    2012-08-15

    Tripterygium wilfordii Hook f. (TWHF) has been demonstrated to have anti-inflammatory, immunosuppressive effects and its clinical use was restricted to some extent due to some toxic effects on the digestive, urogenital, and blood circulatory systems, especially the male reproductive system. In the previous study, we had confirmed that TWHF-loaded solid lipid nanoparticles (SLN) have protective effects on male reproductive toxicity in rats. Anti-inflammatory effects and hepatotoxicity of TWHF-SLN remain to be unidentified. The present study was focused on the anti-inflammatory effect of complete Freund's adjuvant-induced arthritis in rats treated with TWHF-SLN as well as the effects of SLN delivery system on decreasing the hepatotoxicity induced by tripterygium. Sixty-four healthy male rats were randomly divided into eight groups with eight rats each. From day 18 after FCA injection, TWHF-SLN group (120, 60, 30 mg/kg) and TWHF group (120, 60, 30 mg/kg) were administered by oral gavage for 24 consecutive days. The control group was with saline and model control group was without any treatment. The volume of the right hind paws was evaluated at 0, 4, 8, 12, 18, 24, 30, 36 and 42 days post-injection of FCA by a home-made connected device. The serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total bilirubin (TBIL) and albumin (ALB) levels were evaluated by an autoanalyzer. Activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) malondialdehyde (MDA) and xanthine oxidase (XOD) levels were determined using commercial kits. The PG level in sera was examined by double antibody sandwich method. Tissue histopathology was evaluated with hematoxylin and eosin (H&E). The results show that TWHF-SLN can significantly reduce rat paw volume at 60 mg/kg (psystem can enhance the anti-inflammatory activity of TWHF, and meanwhile has a protective effect against TWHF-induced

  8. Sulforaphane Modulates Joint Inflammation in a Murine Model of Complete Freund’s Adjuvant-Induced Mono-Arthritis

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    João Francisco Silva Rodrigues

    2018-04-01

    Full Text Available Rheumatoid arthritis (RA is characterized by inflammation of one or more joints, and affects ~1% of the adult population worldwide. Sulforaphane (SFN is a natural compound that has been suggested as an antioxidant. Here, SFN’s effects were evaluated in a murine mono-arthritis model. Mono-arthritis was induced in mice by a single intra-articular injection of Complete Freund’s Adjuvant (CFA-10 µg/joint, in 10 µL into the ipsilateral joint. The contralateral joint received an equal volume of PBS. On the 4th day post-joint inflammation induction, animals received either SFN (10 mg/kg or vehicle (3% DMSO in saline, intraperitoneally (i.p., twice a day for 3 days. Joint swelling and secondary mechanical allodynia and hyperalgesia were evaluated over 7 days post-CFA. After this period, animals were culled and their blood and synovial fluid samples were collected for analysis of cell populations, cytokine release and thioredoxin reductase (TrxR activity. Knee joint samples were also collected for histology. SFN reduced joint swelling and damage whilst increasing the recruitment of Ly6C+ and Ly6G+ cells to CFA-injected joints. SFN-treated animals presented down-regulation of CD11b and CD62L on synovial fluid Ly6G+ cells. Synovial fluid samples obtained from CFA-injected joints and plasma samples of SFN-treated mice presented higher levels of IL-6 and increased activity of TrxR, in comparison with controls. These results indicate that SFN reduces knee joint damage by modulating cell activation/migration to the joints, cytokine production and increasing the activity of TrxR, and therefore, may represent an alternative treatment to joint inflammation.

  9. Duration of immunity induced by an equine influenza and tetanus combination vaccine formulation adjuvanted with ISCOM-Matrix.

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    Heldens, J G M; Pouwels, H G W; Derks, C G G; Van de Zande, S M A; Hoeijmakers, M J H

    2010-10-08

    Equine influenza is a contagious disease caused by equine influenza virus which belongs to the orthomyxovirus family. Outbreaks of equine influenza cause severe economic loses to the horse industry and consequently horses in competition are required to be regularly vaccinated against equine influenza. Unlike the existing inactivated vaccines, Equilis Prequenza Te is the only one able to induce protection against clinical disease and virus excretion after a primary vaccination course consisting of two vaccine applications 4-6 weeks apart until the recommended time of the third vaccination. In this paper we describe the duration of immunity profile, tested in an experimental setting according to European legislation, of this inactivated equine influenza and tetanus combination vaccine. In addition to influenza antigen, the formulation contains a second generation ISCOM (the so called ISCOMatrix) as an adjuvant. The vaccine aims at the induction of protection from the primary vaccination course until the time of annual revaccination 12 months later, against challenge with a virulent equine influenza strain. The protection against A/equine/Kentucky/95 (H3N8) at the time of annual revaccination was evidenced by a significant reduction of clinical signs of influenza, a significant reduction of virus excretion and a significant reduction of fever. The effect of the annual revaccination on the duration of immunity against influenza and tetanus was also studied by serology. For tetanus, as a consequence of the 24 months duration of immunity, an alternating annual vaccination schedule consisting of Prequenza and Prequenza Te is proposed after the first three doses of Prequenza Te. Copyright © 2010 Elsevier Ltd. All rights reserved.

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

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    Eun-Do Kim

    Full Text Available 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.

  11. Enhanced expressions of mRNA for neuropeptide Y and interleukin 1 beta in hypothalamic arcuate nuclei during adjuvant arthritis-induced anorexia in Lewis rats.

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    Stofkova, Andrea; Haluzik, Martin; Zelezna, Blanka; Kiss, Alexander; Skurlova, Martina; Lacinova, Zdenka; Jurcovicova, Jana

    2009-01-01

    Food intake is activated by hypothalamic orexigenic neuropeptide Y (NPY), which is mainly under the dual control of leptin and ghrelin. Rat adjuvant arthritis (AA), similarly as human rheumatoid arthritis, is associated with cachexia caused by yet unknown mechanisms. The aim of our study was to evaluate NPY expression in hypothalamic arcuate nuclei (nARC) under the conditions of AA-induced changes in leptin, ghrelin and adiponectin. Since IL-1beta is involved in the central induction of anorexia, we studied its expression in the nARC as well. AA was induced to Lewis rats using complete Freund's adjuvant. On days 12, 15 and 18 after complete Freund's adjuvant injection, the levels of leptin, adiponectin, ghrelin and IL-1beta were determined by RIA or ELISA. The mRNA expressions for NPY, leptin receptor (OB-R), ghrelin receptor (Ghsr) and IL-1beta were determined by TaqMan RT-PCR from isolated nARC. In AA rats, decreased appetite, body mass and epididymal fat stores positively correlated with reduced circulating and epididymal fat leptin and adiponectin. Ghrelin plasma levels were increased. In nARC, mRNA for OB-R, Ghsr and NPY were overexpressed in AA rats. AA rats showed overexpression of mRNA for IL-1beta in nARC while circulating, and spleen IL-1beta was unaltered. During AA, overexpression of orexigenic NPY mRNA in nARC along with enhanced plasma ghrelin and lowered leptin levels occur. Decreased food intake indicates a predominant effect of the anorexigenic pathway. Activated expression of IL-1beta in nARC suggests its role in keeping AA-induced anorexia in progress. The reduction in adiponectin may also contribute to AA-induced anorexia. Copyright 2009 S. Karger AG, Basel.

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

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    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*02:01-restricted, cytotoxic T lymphocyte (CTL) epitope derived from influenza A virus. HLA-A*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. © 2013 Elsevier Inc. All rights reserved.

  13. vaccination using profilin and NetB proteins in Montanide IMS adjuvant increases protective immunity against experimentally-induced necrotic enteritis

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    Hyun Soon Lillehoj

    2017-10-01

    Full Text Available Objective The effects of vaccinating 18-day-old chicken embryos with the combination of recombinant Eimeria profilin plus Clostridium perfringens (C. perfringens NetB proteins mixed in the Montanide IMS adjuvant on the chicken immune response to necrotic enteritis (NE were investigated using an Eimeria maxima (E. maxima/C. perfringens co-infection NE disease model that we previously developed. Methods Eighteen-day-old broiler embryos were injected with 100 μL of phosphate-buffered saline, profilin, profilin plus necrotic enteritis B-like (NetB, profilin plus NetB/Montanide adjuvant (IMS 106, and profilin plus Net-B/Montanide adjuvant (IMS 101. After post-hatch birds were challenged with our NE experimental disease model, body weights, intestinal lesions, serum antibody levels to NetB, and proinflammatory cytokine and chemokine mRNA levels in intestinal intraepithelial lymphocytes were measured. Results Chickens in ovo vaccinated with recombinant profilin plus NetB proteins/IMS106 and recombinant profilin plus NetB proteins/IMS101 showed significantly increased body weight gains and reduced gut damages compared with the profilin-only group, respectively. Greater antibody response to NetB toxin were observed in the profilin plus NetB/IMS 106, and profilin plus NetB/IMS 101 groups compared with the other three vaccine/adjuvant groups. Finally, diminished levels of transcripts encoding for proinflammatory cytokines such as lipopolysaccharide-induced tumor necrosis factor-α factor, tumor necrosis factor superfamily 15, and interleukin-8 were observed in the intestinal lymphocytes of chickens in ovo injected with profilin plus NetB toxin in combination with IMS 106, and profilin plus NetB toxin in combination with IMS 101 compared with profilin protein alone bird. Conclusion These results suggest that the Montanide IMS adjuvants potentiate host immunity to experimentally-induced avian NE when administered in ovo in conjunction with the profilin and

  14. Is basic research providing answers if adjuvant anti-estrogen treatment of breast cancer can induce cognitive impairment?

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    Buwalda, Bauke; Schagen, Sanne B.

    2013-01-01

    Adjuvant treatment of cancer by chemotherapy is associated with cognitive impairment in some cancer survivors. Breast cancer patients are frequently also receiving endocrine therapy with selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs) to suppress the growth of

  15. Efficacy of Curcumin as Adjuvant Therapy to Induce or Maintain Remission in Ulcerative Colitis Patients: an Evidence-based Clinical Review

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    Marcellus Simadibrata

    2018-01-01

    Full Text Available Background: treatment guidelines for ulcerative colitis (UC not yet established. Currently, mesalazine, corticosteroids, and immunomodulators are treatment options for UC. However, they are known to have unpleaseant side effects such as nausea, vomiting, headaches, hepatitis, and male infertility. Curcumin is found in Turmeric plants (Curcuma longa L., which possesses both anti-inflammatory and antioxidant properties. This study aimed to determine whether curcumin as adjuvant therapy can induce or maintain remission in UC patients. Methods: structured search in three database (Cochrane, PubMed, Proquest using “Curcumin”, “remission” and “Ulcerative Colitis” as keywords. Inclusion criteria is randomized controlled trials (RCTs, meta-analysis, or systematic review using curcumin as adjuvant therapy in adult UC patients. Results: we found 49 articles. After exclusion, three RCTs were reviewed; two examined curcumin efficacy to induce remission and one for remision maintenance in UC. Curcumin was significantly more effective than placebo in all RCTs. The efficacy of curcumin could be explained by its anti-inflammatory properties, which inhibit NF-kB pathway. Regulation of oxidant/anti-oxidant balance can modify the release of cytokines. However, methods varied between RCTs. Therefore, they cannot be compared objectively. Futhermore, the sample size were small (n= 50, 45, 89 therefore the statistical power was not enough to generate representative results in all UC patients. Conclusion: Available evidence showed that curcumin has the potential to induce and maintain remission in UC patients with no serious side effects. However, further studies with larger sample size are needed to recommend it as adjuvant therapy of ulcerative colitis.

  16. Soluble Dietary Fibers Can Protect the Small Intestinal Mucosa Without Affecting the Anti-inflammatory Effect of Indomethacin in Adjuvant-Induced Arthritis Rats.

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    Satoh, Hiroshi; Matsumoto, Hiroki; Hirakawa, Tomoe; Wada, Naoki

    2016-01-01

    How to prevent the small intestinal damage induced by NSAIDs is an urgent issue to be resolved. In the present study, we examined the effects of soluble dietary fibers on both anti-inflammatory and ulcerogenic effects of indomethacin in arthritic rats. Male Wistar rats weighing 180-220 g were used. Arthritis was induced by injecting Freund's complete adjuvant (killed M. tuberculosis) into the plantar region of the right hindpaw. The animals were fed a regular powder diet for rats or a diet supplemented with soluble dietary fibers such as pectin or guar gum. Indomethacin was administered once a day for 3 days starting 14 days after the adjuvant injection, when marked arthritis was observed. The volumes of the hindpaw were measured before and after indomethacin treatment to evaluate the effect of indomethacin on edema. The lesions in the small intestine were examined 24 h after the final dosing of indomethacin. Hindpaw volume was increased about 3 times 14 days after injection of the adjuvant. Indomethacin (3-10 mg/kg, p.o.) decreased hindpaw volume dose-dependently, but caused severe lesions in the small intestine at doses of 6 and 10 mg/kg. The addition of pectin (1-10 %) or guar gum (10 %) to the diet markedly decreased the lesion formation without affecting the anti-edema action of indomethacin. The same effects of pectin were observed when indomethacin was administered subcutaneously. It is suggested that soluble dietary fibers can prevent intestinal damage induced by NSAIDs without affecting the anti-inflammatory effect of these agents.

  17. Epigenetic suppression of potassium-chloride co-transporter 2 expression in inflammatory pain induced by complete Freund's adjuvant (CFA).

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    Lin, C-R; Cheng, J-K; Wu, C-H; Chen, K-H; Liu, C-K

    2017-02-01

    Multiple mechanisms contribute to the stimulus-evoked pain hypersensitivity that may be experienced after peripheral inflammation. Persistent pathological stimuli in many pain conditions affect the expression of certain genes through epigenetic alternations. The main purpose of our study was to investigate the role of epigenetic modification on potassium-chloride co-transporter 2 (KCC2) gene expression in the persistence of inflammatory pain. Persistent inflammatory pain was induced through the injection of complete Freund's adjuvant (CFA) in the left hind paw of rats. Acetyl-histone H3 and H4 level was determined by chromatin immunoprecipitation in the spinal dorsal horn. Pain behaviour and inhibitory synaptic function of spinal cord were determined before and after CFA injection. KCC2 expression was determined by real time RT-PCR and Western blot. Intrathecal KCC2 siRNA (2 μg per 10 μL per rat) or HDAC inhibitor (10 μg per 10 μL per rat) was injected once daily for 3 days before CFA injection. Persistent inflammatory pain epigenetically suppressed KCC2 expression through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in decreased inhibitory signalling efficacy. KCC2 knock-down caused by intrathecal administration of KCC2 siRNA in naïve rats reduced KCC2 expression in the spinal cord, leading to sensitized pain behaviours and impaired inhibitory synaptic transmission in their spinal cords. Moreover, intrathecal HDAC inhibitor injection in CFA rats increased KCC2 expression, partially restoring the spinal inhibitory synaptic transmission and relieving the sensitized pain behaviour. These findings suggest that the transcription of spinal KCC2 is regulated by histone acetylation epigenetically following CFA. Persistent pain suppresses KCC2 expression through HDAC-mediated histone hypoacetylation and consequently impairs the inhibitory function of inhibitory interneurons. Drugs such as HDAC inhibitors that suppress the influences of

  18. Recombinant in vitro assembled hepatitis C virus core particles induce strong specific immunity enhanced by formulation with an oil-based adjuvant

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    NELSON ACOSTA-RIVERO

    2009-01-01

    Full Text Available In the present work, immunogenicity of recombinant in vitro assembled hepatitis C virus core particles, HCcAg.120-VLPs, either alone or in combination with different adjuvants was evaluated in BALB/c mice. HCcAg.120-VLPs induced high titers of anti-HCcAg.120 antibodies and virus-specific cellular immune responses. Particularly, HCcAg.120-VLPs induced specific delayed type hypersensitivity, and generated a predominant T helper 1 cytokine pro file in immunized mice. In addition, HCcAg.120-VLPs prime splenocytes proliferate in vitro against different HCcAg.120-specific peptides, depending on either the immunization route or the adjuvant used. Remarkably, immunization with HCcAg.120-VLPs/Montanide ISA888 formulation resulted in a significant control of vaccinia virus titer in mice after challenge with a recombinant vaccinia virus expressing HCV core protein, vvCore. Animals immunized with this formulation had a marked increase in the number of IFN-γ producing spleen cells, after stimulation with P815 cells infected with vvCore. These results suggest the use of recombinant HCV core particles as components of therapeutic or preventive vaccine candidates against HCV.

  19. Adjuvant-Associated Peripheral Blood mRNA Profiles and Kinetics Induced by the Adjuvanted Recombinant Protein Candidate Tuberculosis Vaccine M72/AS01 in Bacillus Calmette–Guérin-Vaccinated Adults

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    Robert A. van den Berg

    2018-03-01

    Full Text Available Systems biology has the potential to identify gene signatures associated with vaccine immunogenicity and protective efficacy. The main objective of this study was to identify optimal postvaccination time points for evaluating peripheral blood RNA expression profiles in relation to vaccine immunogenicity and potential efficacy in recipients of the candidate tuberculosis vaccine M72/AS01. In this phase II open-label study (NCT01669096; https://clinicaltrials.gov/, healthy Bacillus Calmette–Guérin-primed, HIV-negative adults were administered two doses (30 days apart of M72/AS01. Twenty subjects completed the study and 18 subjects received two doses. Blood samples were collected pre-dose 1, pre-dose 2, and 1, 7, 10, 14, 17, and 30 days post-dose 2. RNA expression in whole blood (WB and peripheral blood mononuclear cells (PBMCs was quantified using microarray technology. Serum interferon-gamma responses and M72-specific CD4+ T cell responses to vaccination, and the observed safety profile were similar to previous trials. Two different approaches were utilized to analyze the RNA expression data. First, a kinetic analysis of RNA expression changes using blood transcription modules revealed early (1 day post-dose 2 activation of several pathways related to innate immune activation, both in WB and PBMC. Second, using a previously identified gene signature as a classifier, optimal postvaccination time points were identified. Since M72/AS01 efficacy remains to be established, a PBMC-derived gene signature associated with the protective efficacy of a similarly adjuvanted candidate malaria vaccine was used as a proxy for this purpose. This approach was based on the assumption that the AS01 adjuvant used in both studies could induce shared innate immune pathways. Subjects were classified as gene signature positive (GS+ or gene signature negative (GS−. Assignments of subjects to GS+ or GS− groups were confirmed by significant differences in RNA

  20. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    International Nuclear Information System (INIS)

    Chintamani; Singhal, Vinay; Singh, JP; Lyall, Ashima; Saxena, Sunita; Bansal, Anju

    2004-01-01

    Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins) brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio). Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide) were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was assessed using chi-square test and coefficient

  1. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

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    Singh JP

    2004-08-01

    Full Text Available Abstract Background Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. Methods 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio. Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was

  2. Anti-arthritic activity of cell wall content of Lactobacillus plantarum in freund's adjuvant-induced arthritic rats: involvement of cellular inflammatory mediators and other biomarkers.

    Science.gov (United States)

    Gohil, Priyanshee; Patel, Vimal; Deshpande, Shrikalp; Chorawala, Mehul; Shah, Gaurang

    2018-02-01

    Alteration of microbiota is related with rheumatoid arthritis (RA) and administration of certain probiotics showed an improvement in RA. The present study was designed to find out the anti-arthritic activity of cell wall content of Lactobacillus plantarum in complete Freund's adjuvant (CFA)-induced arthritis in rats. Freund's adjuvant was injected into the left footpad in female rats on day 0 and dexamethasone (1 mg kg -1 , s.c.) & cell wall content of L. plantarum (10 5 , 10 7 , and 10 9  cfu/animal, s.c.) treatment were given from day 7 to 21. The change in body weight, paw volume and arthritic index, joint stiffness, gait test, mobility test, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) level, serum rheumatoid factor (RF), and serum TNF-α was measured on day 21. Cell wall content of L. plantarum treated animals showed improvement in all the parameters as compared to that in CFA-treated animals and exert anti-arthritic activity.

  3. A pilot randomized controlled trial of D-cycloserine and distributed practice as adjuvants to constraint-induced movement therapy after stroke.

    Science.gov (United States)

    Nadeau, Stephen E; Davis, Sandra E; Wu, Samuel S; Dai, Yunfeng; Richards, Lorie G

    2014-01-01

    Background. Phase III trials of rehabilitation of paresis after stroke have proven the effectiveness of intensive and extended task practice, but they have also shown that many patients do not qualify, because of severity of impairment, and that many of those who are treated are left with clinically significant deficits. Objective. To test the value of 2 potential adjuvants to normal learning processes engaged in constraint-induced movement therapy (CIMT): greater distribution of treatment over time and the coadministration of d-cycloserine, a competitive agonist at the glycine site of the N-methyl-D-aspartate glutamate receptor. Methods. A prospective randomized single-blind parallel-group trial of more versus less condensed therapy (2 vs 10 weeks) and d-cycloserine (50 mg) each treatment day versus placebo (in a 2 × 2 design), as potential adjuvants to 60 hours of CIMT. Results. Twenty-four participants entered the study, and 22 completed it and were assessed at the completion of treatment and 3 months later. Neither greater distribution of treatment nor treatment with d-cycloserine significantly augmented retention of gains achieved with CIMT. Conclusions. Greater distribution of practice and treatment with d-cycloserine do not appear to augment retention of gains achieved with CIMT. However, concentration of CIMT over 2 weeks ("massed practice") appears to confer no advantage either. © The Author(s) 2014.

  4. Evaluation of the concomitant use of methotrexate and curcumin on Freund's complete adjuvant-induced arthritis and hematological indices in rats.

    Science.gov (United States)

    Banji, David; Pinnapureddy, Jyothi; Banji, Otilia J F; Kumar, A Ranjith; Reddy, K Narsi

    2011-09-01

    To evaluate the concomitant administration of methotrexate and curcumin for antiarthiritic activity in rats. Arthritis was induced in rats following a single subplantar injection of Freund's complete adjuvant (0.1 ml). Rats were divided into six groups of six animals each. Group I and II were control injected with saline and Freund's complete adjuvant (0.1 ml), respectively. Group III arthritic rats were treated with curcumin (100 mg/kg, i.p.) on alternate days. Group IV received methotrexate (MTX) (2 mg/kg, i.p.) once in a week. Group-V and VI were treated with MTX (1 mg/kg, i.p.) once in a week and after 30 min received curcumin (30 mg/kg and 100 mg/kg, thrice a week, i.p.) from 10(th) to 45(th) days, respectively. Body weight and the paw volume was measured on 9(th), 16(th), 23(rd), 30(th), 37(th), and 45(th) days. Determination of complete blood cell counts, hemoglobin concentration, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin concentration was determined on the 46(th) day. An improvement in body weight and a significant (P arthritis was observed with the combination treatment as compared to the positive control. A significant improvement in the hematological profile was also observed in rats treated with curcumin and methotrexate. The study showed a significant anti-arthritic action and protection from hematological toxicity with the combination treatment of methotrexate and curcumin.

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

    International Nuclear Information System (INIS)

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

    2013-01-01

    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 2 and LTB 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 arthritic rats

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

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    Iris Bosschem

    Full Text Available 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Arab, Hany H., E-mail: hany_h_arab@yahoo.com [Biochemistry Division, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taif University, Taif (Saudi Arabia); Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo (Egypt); El-Sawalhi, Maha M. [Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo (Egypt)

    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. In vivo anti-arthritic and anti-nociceptive effects of ethanol extract of Moringa oleifera leaves on complete Freund's adjuvant (CFA)-induced arthritis in rats.

    Science.gov (United States)

    Mahdi, Harith Jameel; Khan, Nurzalina Abdul Karim; Asmawi, Mohd Zaini Bin; Mahmud, Roziahanim; A/L Murugaiyah, Vikneswaran

    2018-03-01

    The medicinal uses of plants are in many cases based exclusively on traditional knowledge without enough scientific evidences. Different parts of Moringa oleifera were traditionally used for the treatment of wide variety of ailments including arthritis and joints pain. The present study had been designed to evaluate the anti-arthritic and anti-nociceptive activities of ethanol extract of Moringa leaves, this being the most abundant plant part suitable for commercial mass production of botanical medicinal products. Complete Freund's adjuvant (CFA)-induced arthritis in rats was used as disease model. CFA-induced inflammatory paw edema, body weight, arthritic index, X-ray radiography, hematological parameters, and walk track and locomotion analysis were all evaluated for the assessment of disease progression. In addition to that, anti-nociceptive activity was examined at different dose levels in both normal and arthritic-induced rats using Eddy's hot plate and tail flick thermal analgesia. The analysis of various arthritic assessment parameters used in this study revealed that Moringa extract has a considerable effect in preventing development or ameliorate arthritis disease severity. Moreover, the ethanol extract of Moringa leaves revealed significant anti-nociceptive activity at in both normal and CFA-induced arthritis rats in a dose-dependent manner. Ethanol extract of Moringa leaves appears to be a really promising as analgesic and arthritis medication, but a larger and more detailed preclinical and clinical studies especially in human is highly recommended.

  9. Adjuvants and Their Mechanisms of Action

    Directory of Open Access Journals (Sweden)

    Masoumeh Foumani

    2012-09-01

    Full Text Available Adjuvants are chemicals, microbial components, or mammalian proteins that enhance the immune response to vaccine antigens. Reducing vaccine-related adverse effects and inducing specific types of immunity has led to the development of numerous new adjuvants. Adjuvants in experimental and commercial vaccines include aluminum salts (alum, oil emulsions, saponins, immune-stimulating complexes (ISCOMs, liposomes, microparticles, nonionic block copolymers, derivatized polysaccharides, cytokines, and a wide variety of bacterial derivatives. The mechanisms of action of these diverse compounds are different. Factors influencing the selection of an adjuvant include animal species, specific pathogen, vaccine antigen, route of immunization, and type of immunity needed. In this paper we review the current adjuvant types, structure and mechanism of action and their application in the design and production of animal and human vaccines to provide a source for students and researchers in related fields .

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

    International Nuclear Information System (INIS)

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

    1991-01-01

    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

  11. Anti-inflammatory and antioxidant effect of Kerabala: a value-added ayurvedic formulation from virgin coconut oil inhibits pathogenesis in adjuvant-induced arthritis.

    Science.gov (United States)

    Ratheesh, M; Sandya, S; Pramod, C; Asha, S; Svenia, Jose P; Premlal, S; GrishKumar, B

    2017-02-01

    Kerabala (CB) is a novel ayurvedic formulation used for treating various inflammatory diseases. This formulation was made from virgin coconut oil and it comprises extracts of Sida cordifolia, coconut milk and sesame oil. The current study was performed to evaluate the anti-inflammatory action of CB on carrageenan-induced acute and adjuvant-induced chronic experimental models. 5 mg/kg bwt was found to be potent dose from carrageenan model and evaluated its effect in adjuvant-induced chronic arthritic model. The antioxidant assays like SOD, catalase, glutathione peroxidase, lipid peroxidation product, nitrate level and GSH were measured in paw tissue. Hematological parameters like hemoglobin (HB) count, ESR, WBC count, plasma CRP levels were analyzed. By RT-PCR, the inflammatory markers like cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) expressions were evaluated. The extracellular matrix proteins like MMP-2 and MMP-9 were determined by zymography and its expression by western blotting. Histopathology and cytology of paw tissue and synovium were analyzed. The result indicated that there was a significant increment in the levels of antioxidant enzymes on CB administration. The hematological markers such as ESR, WBC and plasma CRP levels were reduced by CB treatment and it also increases the HB level. The upregulated gene level expressions of inflammatory markers like COX-2, iNOS, TNF-α and IL-6 were down regulated by administration of CB. MMP-2 and MMP-9 expression significantly reduced by CB administration. Massive influx of inflammatory cell infiltration, proliferative collagen in histological analysis of paw tissue of arthritic rat was decreased by CB administration. Synovial cytology of CB administrated group shows reduced number of reactive mesothelial cells and synovial inflammatory cells. This current study shows that ayurvedic drug CB has an antioxidant, anti-inflammatory and

  12. Adjuvants and delivery systems in veterinary vaccinology: current state and future developments

    DEFF Research Database (Denmark)

    Heegaard, Peter M. H.; Dedieu, Laurence; Johnson, Nicholas

    2011-01-01

    Modern adjuvants should induce strong and balanced immune responses, and it is often desirable to induce specific types of immunity. As an example, efficient Th1-immunity-inducing adjuvants are highly in demand. Such adjuvants promote good cell-mediated immunity against subunit vaccines that have...

  13. Three-dimensional analysis of morphological changes of rat mandibular head induced by administration of adjuvant in mandibular joint cavity

    International Nuclear Information System (INIS)

    Kuroki, Yosuke

    2008-01-01

    Temporal morphological changes of human osteoarthritis (OA) related to temporomandibular joint dysfunction (TMJ) are unknown because of lack of the animal model. The author made the model as in the title. Complete Freud's adjuvant (CFA) was injected in the mandibular joint cavity of male standard deviation (SD) rats with monitoring by X-ray. The site of injection was determined previously with the machine RmCT (in vivo 3D micro-X-ray CT for laboratory animals, Rigaku Corp.), which consisted of rotatable X-ray tube and facing flat panel detector, at whose center anesthetized rat was placed. The machine was also used for observation of the mandible just and 1-14 days after CFA injection and images were processed to 2D and 3D with the software I-view-R (Rigaku Corp.). Morphological changes were seen at 7-14 days on the CT images, and pathologically at 14 days, erosion or osteophytosis in 9/12 animals and enlargement of mandibular head. The cavity treated became larger for 1-14 days persistently. These results indicated that morphological changes accompanying the chronic inflammation had occurred, which was thought useful as a model of TMJ-OA. (R.T.)

  14. Efficacy of cytokine-induced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Yu R

    2017-03-01

    Full Text Available Ruili Yu,1 Bo Yang,2 Xiaohua Chi,3 Lili Cai,4 Cui Liu,5 Lei Yang,6 Xueyan Wang,1 Peifeng He,7 Xuechun Lu2 1Department of Allergy, Beijing Shijitan Hospital, Affiliated to Capital Medical University, 2Department of Geriatric Hematology, Chinese PLA General Hospital, 3Department of Pharmacy, Chinese PLA Rocket Force General Hospital, 4Department of Geriatric Laboratory Medicine, 5Department of Geriatric Ultrasound, 6Medical Department, Nanlou Clinic, Chinese PLA General Hospital, Beijing, 7School of Medical Information Management, Shanxi Medical University, Taiyuan, People’s Republic of China Abstract: This study was designed to evaluate the efficacy and safety of cytokine-induced killer (CIK cell-based immunotherapy as an adjuvant therapy for hepatocellular carcinoma (HCC. Published studies were identified by searching Medline, Cochrane, EMBASE, and Google Scholar databases with the keywords: cytokine-induced killer cell, hepatocellular carcinoma, and immunotherapy. The outcomes of interest were overall survival, progression-free survival, and disease-free survival. Eight randomized controlled trials (RCTs, six prospective studies, and three retrospective studies were included. The overall analysis revealed that patients in the CIK cell-treatment group had a higher survival rate (pooled hazard ratio (HR =0.594, 95% confidence interval [CI] =0.501–0.703, P<0.001. Patients treated with CIK cells in non-RCTs had a higher progression-free survival rate (pooled HR =0.613, 95% CI =0.510–0.738, P<0.001. However, CIK cell-treated patients in RCTs had progression-free survival rates similar to those of the control group (pooled HR =0.700, 95% CI =0.452–1.084, P=0.110. The comparison between pooled results of RCTs and non-RCTs regarding the progression-free survival rate did not reach statistical significance. Patients in the CIK cell-treatment group had lower rates of relapse in RCTs (pooled HR =0.635, 95% CI =0.514–0.784, P<0.001. Similar

  15. Systematic investigation of the role of surfactant composition and choice of oil: Design of a nanoemulsion-based adjuvant inducing concomitant humoral and CD4+ T-cell responses

    DEFF Research Database (Denmark)

    Schmidt, Signe Tandrup; Neustrup, Malene Aaby; Harloff-Helleberg, Stine

    2017-01-01

    humoral immune responses. Therefore, there is an unmet medical need for new adjuvants, which potentiate humoral and CMI responses. The purpose was to design an oil-in-water nanoemulsion adjuvant containing a synthetic CMI-inducing mycobacterial monomycoloyl glycerol (MMG) analogue to concomitantly induce...... humoral and CMI responses. METHODS: The influence of emulsion composition was analyzed using a systematic approach. Three factors were varied: i) saturation of the oil phase, ii) type and saturation of the applied surfactant mixture, and iii) surfactant mixture net charge. RESULTS: The emulsions were...... colloidally stable with a droplet diameter of 150-250 nm, and the zeta-potential correlated closely with the net charge of the surfactant mixture. Only cationic emulsions containing the unsaturated surfactant mixture induced concomitant humoral and CMI responses upon immunization of mice with a Ct antigen...

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

    Science.gov (United States)

    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. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc.

  17. Anti-inflammatory Activity of Ethanol Extract of Beluntas Leaves (Pluchea indica L. on Complete Freund's Adjuvant-induced Inflammatory Model

    Directory of Open Access Journals (Sweden)

    Reza Setiawan Sudirman

    2017-12-01

    Full Text Available A research about anti-inflammatory effect of Beluntas leaves extract on CFA (Complete Freund’s Adjuvant induced inflammatory model has been conducted. The objective of this research was to determine the effect of Beluntas leaves extract in alleviating CFA-induced paw edema in mice (Mus musculus. The number of mice used was 15 and was divided into 5 groups. Group I was treated with NaCMC. Group II, III, and IV were given suspension of Beluntas leaves extract 100 mg/Kg, 300 mg/Kg, and 500 mg/Kg BW, respectively. Group V was a positive control treated with suspension of diclofenac sodium 0.1 ml/10 g orally. The determination of anti-inflammatory potency was based on the average time needed to ameliorate the edema volume. The shortest  time period of edema reduction was produced by diclofenac sodium (within 9.33 days, then followed by Beluntas leaves extract with the concentration of 300 mg/Kg (within 12 days, 500 mg/Kg (within 14.33 days, and 100 mg/Kg (within 17.67 days, consecutively. These results are significantly different compared to negative control group which did not reduce the edema volume during 18 days of observation. In conclusion, ethanol extract of Beluntas leaves has an effective anti-inflamatory effect.

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

    Directory of Open Access Journals (Sweden)

    Kerry L Hilligan

    Full Text Available 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.

  19. Freund's adjuvant-induced inflammation: clinical findings and its effect on hepcidin mRNA expression in horses

    Directory of Open Access Journals (Sweden)

    José P. Oliveira-Filho

    2014-01-01

    Full Text Available Hypoferremia observed during systemic inflammatory disorders is regulated by hepcidin. Hepcidin up-regulation is particularly important during acute inflammation, as it restricts the availability of iron, which is necessary for pathogenic microorganism growth before adaptive immunity occurs. The aim of this study was to evaluate the clinical findings and hepatic hepcidin mRNA expression in horses using a Freund's complete adjuvant (FCA model of inflammation. The expression of hepcidin mRNA in the liver was determined in healthy horses following two intramuscular injections of FCA at 0 h and 12 h. Plasma iron and fibrinogen concentrations were measured at multiple time points between 0 h and 240 h post-FCA injection (PI. Hepcidin mRNA expression was determined by RT-qPCR using liver biopsy samples performed at 0 h (control, 6 h and 18 h PI. The mean plasma fibrinogen level was significantly different from the control values only between 120 and 216 h PI. The mean plasma iron level was significantly lower than the control between 16 and 72 h PI, reaching the lowest levels at 30 h PI (33 % of the initial value, and returned to the reference value from 96 h PI to the end of the experiment. Hepcidin mRNA expression increased at 6 h PI and remained high at 18 h PI. The iron plasma concentration was an earlier indicator of inflammatory processes in horses when compared with fibrinogen and might be useful for the early detection of inflammation in the horse. FCA administration caused the rapid onset of hypoferremia, and this effect was likely the result of up-regulated hepatic hepcidin gene expression. This study emphasizes the importance of hepcidin and iron metabolism during inflammation in horses.

  20. Anti-nociceptive effects of Tanshinone IIA (TIIA) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain.

    Science.gov (United States)

    Sun, Shukai; Yin, Yue; Yin, Xin; Cao, Fale; Luo, Daoshu; Zhang, Ting; Li, Yunqing; Ni, Longxing

    2012-09-01

    Inflammatory pain is an important clinical symptom. The levels of extracellular signal-regulated kinases (ERKs) and the levels of cytokines such as interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play important roles in inflammatory pain. Tanshinone IIA (TIIA) is an important component of Danshen, a traditional Chinese medicine that has been commonly used to treat cardiovascular disease. In this study, we investigated the potential anti-inflammatory nociceptive effects of TIIA on complete Freund's adjuvant (CFA)-induced inflammation and inflammatory pain in rats. The effects of TIIA on CFA-induced thermal and mechanical hypersensitivity were investigated using behavioral tests. The levels of ERKs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transient receptor potential vanilloid 1 (TRPV1) in the fifth segment of the lumbar spinal cord (L5) ganglia were detected by Western blot, and the levels of mRNA and protein production of IL1-β, IL-6 and TNF-α were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immuno sorbent assay (ELISA). In this study, we found that TIIA attenuates the development of CFA-induced mechanical and thermal hypersensitivity. In addition, p-ERK and NF-κB expression levels were inhibited by TIIA, and the levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced. Finally, we found that the expression level of TRPV1 was significantly decreased after TIIA injection. This study demonstrated that TIIA has significant anti-nociceptive effects in a rat model of CFA-induced inflammatory pain. TIIA can inhibit the activation of ERK signaling pathways and the expression of pro-inflammatory cytokines. These results suggest that TIIA may be a potential anti-inflammatory and anti-nociceptive drug. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Role of Sigma-1 Receptor/p38 MAPK Inhibition in Acupoint Catgut Embedding-Mediated Analgesic Effects in Complete Freund's Adjuvant-Induced Inflammatory Pain.

    Science.gov (United States)

    Du, Kairong; Wang, Xue; Chi, Laiting; Li, Wenzhi

    2017-08-01

    The endoplasmic reticulum chaperone protein Sigma-1 receptor (Sig-1 R) and mitogen-activated protein kinases (MAPKs) are involved in the mechanism of pain. Acupoint stimulation exerts an exact antihyperalgesic effect in inflammatory pain. However, whether Sig-1 R and MAPKs are associated with the acupoint stimulation-induced analgesic effects is not clear. This study investigated the analgesic effect of acupoint catgut embedding (ACE) and the inhibition of Sig-1 R and MAPKs in ACE analgesia. Rats were prepared with intrathecal catheter implantation. ACE was applied to bilateral "Kunlun" (BL60), "Zusanli" (ST36), and "Sanyinjiao" (SP6) acupoints in the rat model of inflammatory pain (complete Freund's adjuvant [CFA] intraplantar injection). Then, Sig-1R agonist PRE084 or saline was intrathecally given daily. The paw withdrawal thresholds and paw edema were measured before CFA injection and at 1, 3, and 5 day after CFA injection. Western bolt was used to evaluate the protein expression of spinal Sig-1R, p38MAPK, and extracellular signal-regulated kinase (ERK), and immunohistochemistry of Sig-1R was detected at 1, 3, and 5 days after CFA injection. ACE exhibited specific analgesic effects. ACE increased paw withdrawal thresholds and markedly decreased CFA-induced paw edema at 1, 3, and 5 days. ACE downregulated the protein expression of Sig-1R, which was increased significantly at 1, 3, and 5 days after CFA injection. ACE decreased the expression of p38 MAPK and ERK at 1 and 3 days but not at 5 days. However, an injection of Sig-1R agonist PRE084 markedly reversed these alterations, except ERK expression. The present study demonstrated that ACE exhibited antihyperalgesic effects via the inhibition of the Sig-1R that modulated p38 MAPK, but not ERK, expression in the CFA-induced inflammatory pain model in rats.

  2. Targeting TNF-α and NF-κB activation by bee venom: role in suppressing adjuvant induced arthritis and methotrexate hepatotoxicity in rats.

    Science.gov (United States)

    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. 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.

  3. Nociception contributes to the formation of myogenic contracture in the early phase of adjuvant-induced arthritis in a rat knee.

    Science.gov (United States)

    Kaneguchi, Akinori; Ozawa, Junya; Moriyama, Hideki; Yamaoka, Kaoru

    2017-07-01

    It is unknown how joint contracture is generated in inflamed joints. This study aimed to clarify the role of nociception on the formation of joint contracture secondary to arthritis. Monoarthritis was induced by intra-articular injections of complete Freund's adjuvant (CFA) into rat knees. On day 5 after CFA injection, the passive extension range of motion (ROM) of knee joints were measured, both before and after myotomy of knee flexors, to evaluate the extent of muscular contribution to CFA-induced joint contracture. The steroidal anti-inflammatory drug dexamethasone could prevent ROM restrictions completely, both before and after myotomy. On the other hand, the opioid analgesic drug morphine did not prevent the development of restricted ROM observed after myotomy, while it did before myotomy. This indicates that nociception contributes to joint contracture through alterations in muscular structure (myogenic factors). Next, we tested the hypothesis that nociception-induced reflexive flexor muscle contractions cause myogenic contracture in arthritic joints. To do this, chemical denervation was performed by Botulinum toxin type A (BTX-A) injections into knee flexor muscles, simultaneously with CFA injections into the knee. As expected, BTX-A could alleviate ROM restrictions observed before myotomy. These findings suggest that nociceptive-related muscle contractions play an essential role in the formation of joint contracture. Thus, our study indicates that analgesic management during an early stage of joint arthritis is an essential mean to prevent the formation of joint contracture. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1404-1413, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  4. Intradermal immunization with inactivated swine influenza virus and adjuvant polydi(sodium carboxylatoethylphenoxy)phosphazene (PCEP) induced humoral and cell-mediated immunity and reduced lung viral titres in pigs.

    Science.gov (United States)

    Magiri, Royford; Lai, Ken; Chaffey, Alyssa; Zhou, Yan; Pyo, Hyun-Mi; Gerdts, Volker; Wilson, Heather L; Mutwiri, George

    2018-03-14

    Swine influenza virus is endemic worldwide and it is responsible for significant economic losses to the swine industry. A vaccine that stimulates a rapid and long-lasting protective immune response to prevent this infection is highly sought. Poly[di(sodium carboxylatoethylphenoxy)-phosphazene (PCEP) has demonstrated adjuvant activity when formulated as part of multiple vaccines in mice and pigs. In this study we examined the magnitude and type of immune response induced in pigs vaccinated via the intramuscular or intradermal routes with inactivated swine influenza virus (SIV) H1N1 vaccine formulated with PCEP. Intradermal administration of PCEP-adjuvanted inactivated SIV vaccine stimulated significant anti-SIV antibody titres, increased neutralizing antibodies, and significantly reduced lung virus load with limited reduction of gross lung lesions after challenge with virulent H1N1 relative to control animals. These results indicate that PCEP may be effective as a vaccine adjuvant against swine influenza viruses in pigs and should be considered a potential candidate adjuvant for future swine intradermal influenza vaccines. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Anti-inflammatory and anti-oxidant properties of Curcuma longa (turmeric) versus Zingiber officinale (ginger) rhizomes in rat adjuvant-induced arthritis.

    Science.gov (United States)

    Ramadan, Gamal; Al-Kahtani, Mohammed Ali; El-Sayed, Wael Mohamed

    2011-08-01

    Turmeric (rich in curcuminoids) and ginger (rich in gingerols and shogaols) rhizomes have been widely used as dietary spices and to treat different diseases in Ayurveda/Chinese medicine since antiquity. Here, we compared the anti-inflammatory/anti-oxidant activity of these two plants in rat adjuvant-induced arthritis (AIA). Both plants (at dose 200 mg/kg body weight) significantly suppressed (but with different degrees) the incidence and severity of arthritis by increasing/decreasing the production of anti-inflammatory/pro-inflammatory cytokines, respectively, and activating the anti-oxidant defence system. The anti-arthritic activity of turmeric exceeded that of ginger and indomethacin (a non-steroidal anti-inflammatory drug), especially when the treatment started from the day of arthritis induction. The percentage of disease recovery was 4.6-8.3% and 10.2% more in turmeric compared with ginger and indomethacin (P turmeric over ginger and indomethacin, which may have beneficial effects against rheumatoid arthritis onset/progression as shown in AIA rat model.

  6. Topical Loperamide-Encapsulated Liposomal Gel Increases the Severity of Inflammation and Accelerates Disease Progression in the Adjuvant-Induced Model of Experimental Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Susan Hua

    2017-08-01

    Full Text Available This study evaluates the prophylactic effect of the peripherally-selective mu-opioid receptor agonist, loperamide, administered topically in a liposomal gel formulation on pain, inflammation, and disease progression in the adjuvant-induced model of experimental rheumatoid arthritis in female Lewis rats. In a randomized, blinded and controlled animal trial, AIA rats were divided into six groups consisting of eleven rats per group based on the following treatments: loperamide liposomal gel, free loperamide gel, empty liposomal gel, diclofenac gel (Voltaren®, no treatment, and naive control. Topical formulations were applied daily for a maximum of 17 days—starting from day 0 at the same time as immunization. The time course of the effect of the treatments on antinocieption and inflammation was assessed using a paw pressure analgesiometer and plethysmometer, respectively. Arthritis progression was scored daily using an established scoring protocol. At the end of the study, hind paws were processed for histological analysis. Administration of loperamide liposomal gel daily across the duration of the study produced significant peripheral antinociception as expected; however, increased the severity of inflammation and accelerated arthritis progression. This was indicated by an increase in paw volume, behavioral and observational scoring, and histological analysis compared to the control groups. In particular, histology results showed an increase in pannus formation and synovial inflammation, as well as an upregulation of markers of inflammation and angiogenesis. These findings may have implications for the use of loperamide and other opioids in arthritis and potentially other chronic inflammatory diseases.

  7. In Vivo Detection of the Effect of Electroacupuncture on “Zusanli” Acupoint in Rats with Adjuvant-Induced Arthritis through Optical Coherence Tomography

    Science.gov (United States)

    Yang, Hui; Zhou, Yan; Wu, Xiuli; Su, Chengkang; Long, Jia; Lin, Jin

    2016-01-01

    This study aimed to investigate the effect of electroacupuncture (EA) treatment through optical coherence tomography (OCT) in vivo on rats with adjuvant-induced arthritis. OCT images were obtained from the ankle of the right hind paws of the rats in control, model, and EA groups before modelling and 1 day, 8 days, 15 days, 22 days, and 29 days after modelling. Results demonstrated that the OCT signal of the ankle of the right hind paws of the rats was indistinct compared to 1 day after modelling and before modelling in the EA group. In the EA group, the light averaged attenuation coefficients of the ankle tissues decreased as treatment duration was prolonged after EA was administered (3.43, 2.96, 2.61, 2.42, and 2.29 mm−1, resp.). There was a significant difference in attenuation coefficient decrease between the 29th d and the 1st d for EA group compared with control group (P < 0.01). This condition indicated that the light absorption of the ankle of the treated rats in the EA group decreased. Therefore, OCT can be used to monitor the effect of treatment on rats with arthritis in vivo. PMID:27981046

  8. Proteoliposome derived cochleate as novel adjuvant.

    Science.gov (United States)

    Bracho, Gustavo; Lastre, Miriam; del Campo, Judith; Zayas, Caridad; González, Domingo; Gil, Danay; Acevedo, Reinaldo; Taboada, Carlos; Solís, Rosa L; Pérez, Oliver

    2006-04-12

    Cochleate structures (CS) consist in a highly stable lipid structures that have been reported to be a good antigen delivery system. The incorporation of pathogen associated molecular pattern (PAMP) from bacterial membranes into CS became in a promising approach to develop adjuvants, particularly mucosal adjuvants. Therefore, we prepare CS from proteoliposome (PL) obtained from Neisseria meningitidis B (PLCS) and evaluated it for its capability to stimulate the immune system as well as the adjuvant activity. The ability of PLCS to induce Thl polarization was also explored. The results and the easy capability for new antigen incorporation on CS support its use as adjuvant for immunization with a large variety of pathogen derived antigens and different routes of immunization.

  9. Novel Adjuvants and Immunomodulators for Veterinary Vaccines.

    Science.gov (United States)

    Heegaard, Peter M H; Fang, Yongxiang; Jungersen, Gregers

    2016-01-01

    Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the vaccine is becoming a reality with our increased understanding of innate and adaptive immune activation. This will allow future vaccines to induce immune reactivity having adequate specificity as well as protective and recallable immune effector mechanisms in appropriate body compartments, including mucosal surfaces. Here we describe these new developments and, when possible, relate new immunological knowledge to the many years of experience with traditional, empirical adjuvants. Finally, some protocols are given for production of emulsion (oil-based) and liposome-based adjuvant/antigen formulations.

  10. Research Paper: The Impact of Synovial NF-ĸB Activation on Apoptosis Pattern Change During Adjuvant-induced Inflammation

    Directory of Open Access Journals (Sweden)

    Sahar Golabi

    2017-05-01

    Conclusion: It seems that apoptosis pattern change plays an important role in the progression and modulation of CFA-induced inflammation and its related symptoms. Also, it can be concluded that synovial NF-ĸB had a crucial role in synovial apoptosis change during the study period.

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

    Science.gov (United States)

    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. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc.

  12. Photobiomodulation therapy for the management of radiation-induced dermatitis. A single-institution experience of adjuvant radiotherapy in breast cancer patients after breast conserving surgery

    International Nuclear Information System (INIS)

    Strouthos, Iosif; Chatzikonstantinou, Georgios; Tselis, Nikolaos; Bon, Dimitra; Karagiannis, Efstratios; Zoga, Eleni; Ferentinos, Konstantinos; Maximenko, Julia; Nikolettou-Fischer, Vassiliki; Zamboglou, Nikolaos

    2017-01-01

    Radiation therapy (RT) comprises a key component in the treatment of breast cancer. Radiation-induced skin toxicity is the major adverse event experienced by patients; however, radiodermatitis (RD) prevention and management remains trivial. It is proven that photobiomodulation (PBM) therapy using light-emitting diode (LED) increases wound healing and depicts an anti-inflammatory effect. This single-institute study evaluates the beneficial role of PBM-LED in preventing/reducing RD during breast cancer RT. Of 70 consecutively treated patients, 25 patients were treated with PBM-LED twice a week prior to adjuvant 3D conformal RT after breast-conserving surgery. RD was reported using Common Toxicity Criteria for Adverse Events Version 4.0 and pain intensity using a visual analog scale (VAS). For comparison, a control group (n = 45) received RT without PBM-LED. In addition, a ''matched'' group (n = 25) was generated from the control group based on propensity for potentially confounding variables. In the PBM group, 22 patients (88%) presented grade 1 and 3 (12%) grade 2 RD. In the control group, 25 patients (55.6%) developed grade 1 reactions, 18 patients (40%) grade 2, and 2 (4.4%) patients grade 3 RD. Concerning pain intensity, 15 patients (60%) of the PBM treatment arm reported no pain, 5 patients (20%) VAS 2, and 5 (20%) VAS 3. In the control group, 13 patients (28.9%) reported no pain, 2 (4.4%) VAS 1, 7 (15.6%) VAS 2, 9 patients (20%) reported VAS 3, 12 (26.7%) patients VAS 4, and 2 (4.4%) patients VAS 5. PBM-LED therapy applied prior to RT might be effective in decreasing the incidence and sequelae of radiation-induced skin toxicity in breast cancer patients treated with breast-conserving surgery. (orig.) [de

  13. Role of spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in complete Freund's adjuvant-induced inflammatory pain

    Directory of Open Access Journals (Sweden)

    Shih Ming-Hung

    2008-12-01

    Full Text Available Abstract Spinal cord α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs mediate acute spinal processing of nociceptive and non-nociceptive information, but whether and how their activation contributes to the central sensitization that underlies persistent inflammatory pain are still unclear. Here, we examined the role of spinal AMPARs in the development and maintenance of complete Freund's adjuvant (CFA-induced persistent inflammatory pain. Intrathecal application of two selective non-competitive AMPAR antagonists, CFM-2 (25 and 50 μg and GYKI 52466 (50 μg, significantly attenuated mechanical and thermal hypersensitivities on the ipsilateral hind paw at 2 and 24 h post-CFA injection. Neither CFM-2 nor GYKI 52466 affected the contralateral basal responses to thermal and mechanical stimuli. Locomotor activity was not altered in any of the drug-treated animals. CFA-induced inflammation did not change total expression or distribution of AMPAR subunits GluR1 and GluR2 in dorsal horn but did alter their subcellular distribution. The amount of GluR2 was markedly increased in the crude cytosolic fraction and decreased in the crude membrane fraction from the ipsilateral L4–5 dorsal horn at 24 h (but not at 2 h post-CFA injection. Conversely, the level of GluR1 was significantly decreased in the crude cytosolic fraction and increased in the crude membrane fraction from the ipsilateral L4–5 dorsal horn at 24 h (but not at 2 h post-CFA injection. These findings suggest that spinal AMPARs might participate in the central spinal mechanism of persistent inflammatory pain.

  14. Adjuvanted HLA-supertype restricted subdominant peptides induce new T-cell immunity during untreated HIV-1-infection

    DEFF Research Database (Denmark)

    Karlsson, Ingrid; Brandt, Lea; Vinner, Lasse

    2013-01-01

    . T-cell immunogenicity was examined longitudinally by a flow cytometry (CD107a, IFNγ, TNFα, IL-2 and/or MIP1β expression) as well as IFNγ ELISPOT. Safety was evaluated by clinical follow up combined with monitoring of biochemistry, hematology, CD4 T-cell counts and viral load. New CD4 and CD8 T......-cell responses specific for one or more vaccine epitopes were induced in 10/10 vaccinees. The responses were dominated by CD107a and MIP1β expression. There were no significant changes in HIV-1 viral load or CD4 T-cell counts. Our study demonstrates that the peptide/CAF01 vaccine is safe and that it is possible...

  15. Oxaliplatin-Induced Leukocytoclastic Vasculitis under Adjuvant Chemotherapy for Colorectal Cancer: Two Cases of a Rare Adverse Event

    Directory of Open Access Journals (Sweden)

    Henriette Quack

    2013-12-01

    Full Text Available Leukocytoclastic vasculitis is a multicausal systemic inflammatory disease of the small vessels, histologically characterized by inflammation and deposition of both nuclear debris and fibrin in dermal postcapillary venules. The clinical picture typically involves palpable purpura of the lower legs and may be associated with general symptoms such as fatigue, arthralgia and fever. Involvement of the internal organs, most notably the kidneys, the central nervous system or the eyes, is possible and determines the prognosis. Oxaliplatin-induced leukocytoclastic vasculitis is a very rare event that limits treatment options in affected patients. We report 2 patients who developed the condition under chemotherapy for advanced rectal and metastatic colon carcinoma, respectively; a termination of the therapy was therefore necessary. While current therapies for colorectal cancer include the combination of multimodal treatment with new and targeted agents, rare and unusual side effects elicited by established agents also need to be taken into account for the clinical management.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

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

    2016-01-01

    Abstract 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/m2. 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

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

    Science.gov (United States)

    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.

  19. Chemotherapy-induced nausea and vomiting in Asian women with breast cancer receiving anthracycline-based adjuvant chemotherapy.

    Science.gov (United States)

    Bourdeanu, Laura; Frankel, Paul; Yu, Wai; Hendrix, Gregory; Pal, Sumanta; Badr, Lina; Somlo, George; Luu, Thehang

    2012-01-01

    Chemotherapy-induced nausea and vomiting (CINV) remain among the most frequently reported distressing side effects associated with anthracycline-based chemotherapy despite significant advances in antiemetic management. The main risk factor for severity of CINV is the emetogenic potential of the chemotherapeutic agents. However, patient-related risk factors have been identified, including genetic makeup. Although studies have noted that ethnicity influences nausea and vomiting in other contexts, there is a paucity of research regarding the impact of ethnicity on CINV. This study was undertaken to evaluate whether Asian women receiving anthracycline-based chemotherapy experience more CINV than non-Asians. A retrospective, comparative, correlational chart review was performed to abstract the relevant variables. Data from a convenience sample of 358 women with breast cancer who received chemotherapy with doxorubicin between 2004 and 2008 at City of Hope in Duarte, California, were evaluated. The sample consisted of Caucasians (45%), Hispanics (27.7%), Asians (19.8%), and African Americans (7.5%). The results indicate that Asian women with breast cancer undergoing anthracycline-based chemotherapy experienced statistically significantly more clinically important CINV than their non-Asian counterparts. The data were collected retrospectively, with a certain population distribution at a specific time. This study provides interesting preliminary evidence that Asian ethnicity plays a role in the development of severe CINV. When managing chemotherapy toxicities in women with breast cancer, health-care providers should tailor therapy to individual risk profiles. Specifically, consideration of antiemetic therapy should accommodate patient characteristics, such as Asian descent. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Alternative inactivated poliovirus vaccines adjuvanted with Quillaja brasiliensis or Quil-a saponins are equally effective in inducing specific immune responses.

    Directory of Open Access Journals (Sweden)

    Fernanda de Costa

    Full Text Available Inactivated polio vaccines (IPV have an important role at the final stages of poliomyelitis eradication programs, reducing the risks associated with the use of attenuated polio vaccine (OPV. An affordable option to enhance vaccine immunogenicity and reduce costs of IPV may be the use of an effective and renewable adjuvant. In the present study, the adjuvant activity of aqueous extract (AE and saponin fraction QB-90 from Quillaja brasiliensis using poliovirus antigen as model were analyzed and compared to a preparation adjuvanted with Quil-A, a well-known saponin-based commercial adjuvant. Experimental vaccines were prepared with viral antigen plus saline (control, Quil-A (50 µg, AE (400 µg or QB-90 (50 µg. Sera from inoculated mice were collected at days 0, 28, 42 and 56 post-inoculation of the first dose of vaccine. Serum levels of specific IgG, IgG1 and IgG2a were significantly enhanced by AE, QB-90 and Quil-A compared to control group on day 56. The magnitude of enhancement was statistically equivalent for QB-90 and Quil-A. The cellular response was evaluated through DTH and analysis of IFN-γ and IL-2 mRNA levels using in vitro reestimulated splenocytes. Results indicated that AE and QB-90 were capable of stimulating the generation of Th1 cells against the administered antigen to the same extent as Quil-A. Mucosal immune response was enhanced by the vaccine adjuvanted with QB-90 as demonstrated by increases of specific IgA titers in bile, feces and vaginal washings, yielding comparable or higher titers than Quil-A. The results obtained indicate that saponins from Q. brasiliensis are potent adjuvants of specific cellular and humoral immune responses and represent a viable option to Quil-A.

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

    Science.gov (United States)

    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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. 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

    Science.gov (United States)

    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

  3. The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8(+) T-cell responses

    DEFF Research Database (Denmark)

    Schmidt, Signe Tandrup; Khadke, Swapnil; Korsholm, Karen Smith

    2016-01-01

    A prerequisite for vaccine-mediated induction of CD8(+) T-cell responses is the targeting of dendritic cell (DC) subsets specifically capable of cross-presenting antigen epitopes to CD8(+) T cells. Administration of a number of cationic adjuvants via the intraperitoneal (i.p.) route has been show...

  4. Enhanced expressions of mRNA for neuropeptide Y and interleukin 1 beta in hypothalamic arcuate nuclei during adjuvant arthritis-induced anorexia in Lewis rats

    Czech Academy of Sciences Publication Activity Database

    Stofková, A.; Haluzík, M.; Železná, Blanka; Kiss, A.; Skurlová, M.; Lacinová, Z.; Jurcovicová, J.

    2009-01-01

    Roč. 16, č. 6 (2009), s. 377-384 ISSN 1021-7401 R&D Projects: GA ČR GA305/06/0427 Institutional research plan: CEZ:AV0Z40550506 Keywords : adjuvant arthritis * anorexia * leptin * adiponectin Subject RIV: CC - Organic Chemistry Impact factor: 2.034, year: 2009

  5. Incidence of cold-induced peripheral neuropathy and dose modification of adjuvant oxaliplatin-based chemotherapy for patients with colorectal cancer

    DEFF Research Database (Denmark)

    Altaf, Rahim; Lund Brixen, Annette; Kristensen, Bent

    2014-01-01

    BACKGROUND: The CAPOX regimen is used for adjuvant treatment of colorectal cancer. A well-known side effect of oxaliplatin, which often leads to dose modification (DM), is acute neuropathy (AN). AN is provoked by cold, and it could therefore be expected that the degree of AN and thereby DM is more...

  6. In ovo vaccines based on recombinant NetB toxin and Montanide IMS adjuvants induced protective immunity against Necrotic Enteritis in chickens

    Science.gov (United States)

    The current study was conducted to investigate the effects of in ovo injection of recombinant clostridium NetB toxin plus Eimeria profilin proteins in combination with Montanide adjuvants in modulating immune system in chickens infected for experimental necrotic enteritis (NE) disease. Broiler eggs ...

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

    Directory of Open Access Journals (Sweden)

    Freek Cox

    Full Text Available 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.

  8. The adjuvant potential of synthetic alkylglycerols.

    Science.gov (United States)

    Acevedo, Reinaldo; Gil, Danay; del Campo, Judith; Bracho, Gustavo; Valdés, Yolanda; Pérez, Oliver

    2006-04-12

    Alkylglycerols (AGs) have shown immune stimulant and adjuvant activity in many studies, but natural sources are not so accessible and their extraction from them is very complicated. Therefore, a group of chemists at IFAL have synthesized AG analogs. The aim of this work was to evaluate the adjuvant potential of different synthetic AGs. A mix of ovoalbumin (Ova) and AGs increase anti-Ova IgG antibodies production in sera of immunized mice. The predominant subclass was IgG1 although higher levels of IgG2a were observed as the carbon chain length of AGs increased. AGs also induced the production of IL-12 and nitric oxide (NO) in the U937 human histiocyte and J774 mouse macrophage cell lines, respectively. These results indicate that synthetic AGs are effective adjuvants for the standardized antigen, Ova.

  9. MF59- and Al(OH3-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.

    Directory of Open Access Journals (Sweden)

    Elisabetta eMonaci

    2015-09-01

    Full Text Available Staphylococcus aureus (S. aureus is an important opportunistic pathogen that may cause invasive life-threatening infections like sepsis and pneumonia. Due to 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.

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

    Science.gov (United States)

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

    2014-06-05

    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

  11. Photobiomodulation therapy for the management of radiation-induced dermatitis. A single-institution experience of adjuvant radiotherapy in breast cancer patients after breast conserving surgery

    Energy Technology Data Exchange (ETDEWEB)

    Strouthos, Iosif [Sana Klinikum Offenbach, Department of Radiation Oncology, Offenbach (Germany); Medical Center - Albert Ludwigs University of Freiburg, Department of Radiotherapy and Oncology, Freiburg (Germany); Chatzikonstantinou, Georgios; Tselis, Nikolaos [Sana Klinikum Offenbach, Department of Radiation Oncology, Offenbach (Germany); J.W. Goethe University, Department of Radiotherapy and Oncology, Frankfurt am Main (Germany); Bon, Dimitra [J.W. Goethe University, Institute of Biostatistics and Mathematical Modelling, Frankfurt am Main (Germany); Karagiannis, Efstratios [Sana Klinikum Offenbach, Department of Radiation Oncology, Offenbach (Germany); Otto von Guericke University, Department of Radiation Oncology, Magdeburg (Germany); Zoga, Eleni; Ferentinos, Konstantinos; Maximenko, Julia; Nikolettou-Fischer, Vassiliki; Zamboglou, Nikolaos [Sana Klinikum Offenbach, Department of Radiation Oncology, Offenbach (Germany)

    2017-06-15

    Radiation therapy (RT) comprises a key component in the treatment of breast cancer. Radiation-induced skin toxicity is the major adverse event experienced by patients; however, radiodermatitis (RD) prevention and management remains trivial. It is proven that photobiomodulation (PBM) therapy using light-emitting diode (LED) increases wound healing and depicts an anti-inflammatory effect. This single-institute study evaluates the beneficial role of PBM-LED in preventing/reducing RD during breast cancer RT. Of 70 consecutively treated patients, 25 patients were treated with PBM-LED twice a week prior to adjuvant 3D conformal RT after breast-conserving surgery. RD was reported using Common Toxicity Criteria for Adverse Events Version 4.0 and pain intensity using a visual analog scale (VAS). For comparison, a control group (n = 45) received RT without PBM-LED. In addition, a ''matched'' group (n = 25) was generated from the control group based on propensity for potentially confounding variables. In the PBM group, 22 patients (88%) presented grade 1 and 3 (12%) grade 2 RD. In the control group, 25 patients (55.6%) developed grade 1 reactions, 18 patients (40%) grade 2, and 2 (4.4%) patients grade 3 RD. Concerning pain intensity, 15 patients (60%) of the PBM treatment arm reported no pain, 5 patients (20%) VAS 2, and 5 (20%) VAS 3. In the control group, 13 patients (28.9%) reported no pain, 2 (4.4%) VAS 1, 7 (15.6%) VAS 2, 9 patients (20%) reported VAS 3, 12 (26.7%) patients VAS 4, and 2 (4.4%) patients VAS 5. PBM-LED therapy applied prior to RT might be effective in decreasing the incidence and sequelae of radiation-induced skin toxicity in breast cancer patients treated with breast-conserving surgery. (orig.) [German] Radiotherapie (RT) ist integrativer Bestandteil der multimodalen Therapie beim Mammakarzinom. Strahlentherapieinduzierte Hauttoxizitaet ist dabei das haeufigste unerwuenschte Ereignis; dennoch sind Praevention und Management der

  12. Experimental autoimmune glomerulonephritis induced by anti-glomerular basement membrane antibody. II. Effects of injecting heterologous, homologous, or autologous glomerular basement membranes and complete Freund's adjuvant into sheep.

    OpenAIRE

    Steblay, R. W.; Rudofsky, U. H.

    1983-01-01

    The effects of injecting human, rabbit, rat, or single-kidney homologous glomerular basement membrane (GBM) or autologous GBM, each in complete Freund's adjuvant (CFA), into 15- to 18-month-old sheep are compared. All sheep receiving heterologous GBM and 3 of 6 sheep receiving homologous GBM had anti-GBM nephritis, but such sheep did not bind autoantibodies or have Goodpasturelike lesions in their lungs. Sheep given injections of human GBM had autoantibodies to antigenic determinants shared b...

  13. Hypothesis driven development of new adjuvants: short peptides as immunomodulators.

    Science.gov (United States)

    Dong, Jessica C; Kobinger, Gary P

    2013-04-01

    To date, vaccinations have been one of the key strategies in the prevention and protection against infectious pathogens. Traditional vaccines have well-known limitations such as safety and efficacy issues, which consequently deems it inappropriate for particular populations and may not be an effective strategy against all pathogens. This evidence highlights the need to develop more efficacious vaccination regiments. Higher levels of protection can be achieved by the addition of immunostimulating adjuvants. Many adjuvants elicit strong, undefined inflammation, which produces increased immunogenicity but may also lead to undesirable effects. Hypothesis driven development of adjuvants is needed to achieve a more specific and directed immune response required for optimal and safe vaccine-induced immune protection. An example of such hypothesis driven development includes the use of short immunomodulating peptides as adjuvants. These peptides have the ability to influence the immune response and can be extrapolated for adjuvant use, but requires further investigation.

  14. 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

    Science.gov (United States)

    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

  15. Laser vaccine adjuvants

    Science.gov (United States)

    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

  16. 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.

    Science.gov (United States)

    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.

  17. 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.

    Science.gov (United States)

    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.

  18. A Glycolipid Adjuvant, 7DW8-5, Enhances CD8+ T Cell Responses Induced by an Adenovirus-Vectored Malaria Vaccine in Non-Human Primates

    OpenAIRE

    Padte, Neal N.; Boente-Carrera, Mar; Andrews, Chasity D.; McManus, Jenny; Grasperge, Brooke F.; Gettie, Agegnehu; Coelho-dos-Reis, Jordana G.; Li, Xiangming; Wu, Douglass; Bruder, Joseph T.; Sedegah, Martha; Patterson, Noelle; Richie, Thomas L.; Wong, Chi-Huey; Ho, David D.

    2013-01-01

    A key strategy to a successful vaccine against malaria is to identify and develop new adjuvants that can enhance T-cell responses and improve protective immunity. Upon co-administration with a rodent malaria vaccine in mice, 7DW8-5, a recently identified novel analog of α-galactosylceramide (α-GalCer), enhances the level of malaria-specific protective immune responses more strongly than the parent compound. In this study, we sought to determine whether 7DW8-5 could provide a similar potent ad...

  19. Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir.

    Science.gov (United States)

    Hensel, Michael T; Marshall, Jason D; Dorwart, Michael R; Heeke, Darren S; Rao, Eileen; Tummala, Padmaja; Yu, Li; Cohen, Gary H; Eisenberg, Roselyn J; Sloan, Derek D

    2017-05-01

    Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonists in vivo In mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted most robust, functional HSV-2 antigen-specific CD8 T cell responses and high titers of neutralizing antibodies, demonstrating its superiority to vaccines adjuvanted by monophosphoryl lipid A (MPL)-alum. We further established that FI-HSV-2 alone or in combination with adjuvants as well as adjuvanted subunit vaccines were successful in the induction of NAbs and T cell responses in guinea pigs. These immunological responses were coincident with a suppression of vaginal HSV-2 shedding, low lesion scores, and a reduction in latent HSV-2 DNA in dorsal root ganglia to undetectable levels. These data support the further preclinical and clinical development of prophylactic HSV-2 vaccines that contain appropriate antigen and adjuvant components responsible for programming elevated CD8 T cell responses. IMPORTANCE Millions of people worldwide are infected with herpes simplex virus 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors

  20. Immunization with Tc52 or its amino terminal domain adjuvanted with c-di-AMP induces Th17+Th1 specific immune responses and confers protection against Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    Marina N Matos

    2017-02-01

    Full Text Available The development of new adjuvants enables fine modulation of the elicited immune responses. Ideally, the use of one or more adjuvants should result in the induction of a protective immune response against the specific pathogen. We have evaluated the immune response and protection against Trypanosoma cruzi infection in mice vaccinated with recombinant Tc52 or its N- and C-terminal domains (NTc52 and CTc52 adjuvanted either with the STING (Stimulator of Interferon Genes agonist cyclic di-AMP (c-di-AMP, a pegylated derivative of α-galactosylceramide (αGC-PEG, or oligodeoxynucleotides containing unmethylated CpG motifs (ODN-CpG. All groups immunized with the recombinant proteins plus adjuvant: Tc52+c-di-AMP, NTc52+c-di-AMP, CTc52+c-di-AMP, NTc52+c-di-AMP+αGC-PEG, NTc52+CpG, developed significantly higher anti-Tc52 IgG titers than controls. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 showed the highest Tc52-specific IgA titers in nasal lavages. All groups immunized with the recombinant proteins plus adjuvant developed a strong specific cellular immune response in splenocytes and lymph node cells with significant differences for groups immunized with c-di-AMP and Tc52, NTc52 or CTc52. These groups also showed high levels of Tc52-specific IL-17 and IFN-γ producing cells, while NTc52+CpG group only showed significant difference with control in IFN-γ producing cells. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 developed predominantly a Th17 and Th1immune response, whereas for NTc52+CpG it was a dominant Th1 response. It was previously described that αGC-PEG inhibits Th17 differentiation by activating NKT cells. Thus, in this work we have also included a group immunized with both adjuvants (NTc52+c-di-AMP+αGC-PEG with the aim to modulate the Th17 response induced by c-di-AMP. This group showed a significant reduction in the number of Tc52-specific IL-17 producing splenocytes, as compared to the group NTc52+c-di-AMP, which has

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

    Science.gov (United States)

    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. Copyright © 2014. Published by Elsevier Ltd.

  2. Forging a potent vaccine adjuvant: CpG ODN/cationic peptide nanorings.

    Science.gov (United States)

    Gungor, Bilgi; Yagci, Fuat Cem; Gursel, Ihsan; Gursel, Mayda

    Type I interferon inducers may potentially be engineered to function as antiviral and anticancer agents, or alternatively, vaccine adjuvants, all of which may have clinical applications. We recently described a simple strategy to convert a Toll-like receptor 9 (TLR9) agonist devoid of interferon α (IFNα) stimulating activity into a robust Type I interferon inducer with potent vaccine adjuvant activity.

  3. A glycolipid adjuvant, 7DW8-5, enhances CD8+ T cell responses induced by an adenovirus-vectored malaria vaccine in non-human primates.

    Science.gov (United States)

    Padte, Neal N; Boente-Carrera, Mar; Andrews, Chasity D; McManus, Jenny; Grasperge, Brooke F; Gettie, Agegnehu; Coelho-dos-Reis, Jordana G; Li, Xiangming; Wu, Douglass; Bruder, Joseph T; Sedegah, Martha; Patterson, Noelle; Richie, Thomas L; Wong, Chi-Huey; Ho, David D; Vasan, Sandhya; Tsuji, Moriya

    2013-01-01

    A key strategy to a successful vaccine against malaria is to identify and develop new adjuvants that can enhance T-cell responses and improve protective immunity. Upon co-administration with a rodent malaria vaccine in mice, 7DW8-5, a recently identified novel analog of α-galactosylceramide (α-GalCer), enhances the level of malaria-specific protective immune responses more strongly than the parent compound. In this study, we sought to determine whether 7DW8-5 could provide a similar potent adjuvant effect on a candidate human malaria vaccine in the more relevant non-human primate (NHP) model, prior to committing to clinical development. The candidate human malaria vaccine, AdPfCA (NMRC-M3V-Ad-PfCA), consists of two non-replicating recombinant adenoviral (Ad) vectors, one expressing the circumsporozoite protein (CSP) and another expressing the apical membrane antigen-1 (AMA1) of Plasmodium falciparum. In several phase 1 clinical trials, AdPfCA was well tolerated and demonstrated immunogenicity for both humoral and cell-mediated responses. In the study described herein, 25 rhesus macaques received prime and boost intramuscular (IM) immunizations of AdPfCA alone or with an ascending dose of 7DW8-5. Our results indicate that 7DW8-5 is safe and well-tolerated and provides a significant enhancement (up to 9-fold) in malaria-specific CD8+ T-cell responses after both priming and boosting phases, supporting further clinical development.

  4. A glycolipid adjuvant, 7DW8-5, enhances CD8+ T cell responses induced by an adenovirus-vectored malaria vaccine in non-human primates.

    Directory of Open Access Journals (Sweden)

    Neal N Padte

    Full Text Available A key strategy to a successful vaccine against malaria is to identify and develop new adjuvants that can enhance T-cell responses and improve protective immunity. Upon co-administration with a rodent malaria vaccine in mice, 7DW8-5, a recently identified novel analog of α-galactosylceramide (α-GalCer, enhances the level of malaria-specific protective immune responses more strongly than the parent compound. In this study, we sought to determine whether 7DW8-5 could provide a similar potent adjuvant effect on a candidate human malaria vaccine in the more relevant non-human primate (NHP model, prior to committing to clinical development. The candidate human malaria vaccine, AdPfCA (NMRC-M3V-Ad-PfCA, consists of two non-replicating recombinant adenoviral (Ad vectors, one expressing the circumsporozoite protein (CSP and another expressing the apical membrane antigen-1 (AMA1 of Plasmodium falciparum. In several phase 1 clinical trials, AdPfCA was well tolerated and demonstrated immunogenicity for both humoral and cell-mediated responses. In the study described herein, 25 rhesus macaques received prime and boost intramuscular (IM immunizations of AdPfCA alone or with an ascending dose of 7DW8-5. Our results indicate that 7DW8-5 is safe and well-tolerated and provides a significant enhancement (up to 9-fold in malaria-specific CD8+ T-cell responses after both priming and boosting phases, supporting further clinical development.

  5. Immune responses induced in rabbits after oral administration of bovine serum albumin in combination with different adjuvants (herb extracts, aluminium hydroxide and platinum nanoparticles

    Directory of Open Access Journals (Sweden)

    G. Bižanov

    2016-12-01

    Full Text Available The aim of the current study was to evaluate the immunostimulatory activity of 10 different herbal extracts from Vitex agnus-castus, Vinca major, Aloe arborescens and the polyherbal product containing extracts from Sambucus nigra, Primula versis, Pinus alba, Gentiana lutea, Cetraria islandica, Eucaliptus globulus, Citrus limon and aluminium hydroxide, as well as platinum nanoparticles. Rabbits were immunized three times orally with bovine serum albumin (BSA in combination with the components mentioned above. BSA-specific IgA antibodies in saliva and IgG antibodies in serum were examined by ELISA. It was found that the rabbits immunized with BSA in combination with either platinum nanoparticles or aluminium hydroxide had higher titres of BSA-specific IgA antibodies in their saliva at day 56 of observation. Likewise, rabbits treated with BSA and Vinca major or Aloe arborescens extracts showed higher levels of BSA-specific IgG antibodies in the serum at the end of observation. These results suggest that some plant extracts, aluminium hydroxide and platinum nanoparticles components could be used as oral adjuvants or as immunomodulators for rabbits.

  6. 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.

    Science.gov (United States)

    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. Copyright © 2015. Published by Elsevier B.V.

  7. Learning impairment in honey bees caused by agricultural spray adjuvants.

    Directory of Open Access Journals (Sweden)

    Timothy J Ciarlo

    Full Text Available 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

  8. The Suppression of Adjuvant-induced Inflammation and the Inhibition of the Serum and Tissue IL-17, TNF-α and IL-1β levels by Thymol and Carvacrol

    Directory of Open Access Journals (Sweden)

    Nasser Gholijani

    2017-06-01

    Full Text Available Background and Aim: Thymol and carvacrol are two important components of thyme that have multiple medicinal uses. This study investigates the in vivo effects of these natural products on adjuvant-induced inflammation and secretion of interleukin (IL-17 and key inflammatory cytokines in rats. Materials and Methods: We injected complete Freund’s adjuvant (CFA into the hind paws of rats in order to induce inflammation. Each of the CFA-treated rat groups received gavages of thymol, carvacrol, or vehicle (CFA-only group. Rats’ paws and ankle edema were measured and then we were able to determine an inflammatory score based on the results. After 72 h of inflammation induction, sera were collected and subsequently inflamed tissue extracts were prepared for cytokine assay by ELISA. Results: Both components significantly decreased paw edema in rats (p<0.01. Thymol decreased ankle edema to 61.6% of edema in CFA-only rats (p<0.001. We observed a decreased inflammatory score in the thymol and carvacrol-treated rats. The evaluation of the tissue and serum inflammatory cytokine levels showed that both components decreased tumor necrosis factor (TNF-α levels (p<0.05. Thymol and carvacrol reduced interleukin (IL-1β serum and tissue levels, respectively. These components reduced tissue levels of IL-17 from 148.4±13.4pg/ml in CFA-only rats to 90.1±18.9pg/ml (thymol and 82.3±9.2pg/ml (carvacrol. Both components decreased serum IL-17 levels in rats (p<0.05. In comparison, the anti-inflammatory drug, indomethacin, reduced the inflammatory score and decreased tissue TNF-α and IL-1β levels but did not affect IL-17 production. Conclusion: Carvacrol and thymol could relieve inflammation symptoms possibly by downregulating serum and tissue IL-17 expression in addition to key pro-inflammatory cytokines, TNFα and IL-1β.

  9. ERM immersion vaccination and adjuvants

    DEFF Research Database (Denmark)

    Skov, J.; Chettri, J. K.; Jaafar, R. M.

    2015-01-01

    Two candidate adjuvants were tested with a commercial ERM dip vaccine (AquaVac™ Relera, MSD Animal Health) for rainbow trout in an experimental design compatible with common vaccination practices at farm level, i.e. immersion of fish in vaccine (±adjuvant) for 30 s. The adjuvants were...... the commercial product Montanide™ IMS 1312 VG PR (SEPPIC), and a soluble and ≥98% pure β-glucan from yeast (Saccharomyces cerevisiae) (Sigma-Aldrich). Hence, five experimental groups in duplicate were established and exposed to vaccine and adjuvants in the following combinations: AquaVac™ Relera (alone); Aqua......Vac™ Relera + Montanide™; AquaVac™ Relera + β-glucan; Montanide™ (alone); and β-glucan (alone). Approximately 450 degree days post-vaccination, the fish were bath-challenged with live Yersinia ruckeri to produce survival curves. Blood, skin and gills were sampled at selected time points during the course...

  10. Mechanisms of, and Adjuvants for, Bone Pain.

    Science.gov (United States)

    Figura, Nicholas; Smith, Joshua; Yu, Hsiang-Hsuan Michael

    2018-06-01

    Metastatic bone pain is a complex, poorly understood process. Understanding the unique mechanisms causing cancer-induced bone pain may lead to potential therapeutic targets. This article discusses the effects of osteoclast overstimulation within the tumor microenvironment; the role of inflammatory factors at the tumor-nociceptor interface; the development of structural instability, causing mechanical nerve damage; and, ultimately, the neuroplastic changes in the setting of sustained pain. Several adjuvant therapies are available to attenuate metastatic bone pain. This article discusses the role of pharmacologic therapies, surgery, kyphoplasty, vertebroplasty, and radiofrequency ablation. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. A clinically applicable adjuvant for an atherosclerosis vaccine in mice.

    Science.gov (United States)

    Kobiyama, Kouji; Vassallo, Melanie; Mitzi, Jessica; Winkels, Holger; Pei, Hong; Kimura, Takayuki; Miller, Jacqueline; Wolf, Dennis; Ley, Klaus

    2018-06-22

    Vaccination with MHC-II-restricted peptides from Apolipoprotein B (ApoB) with complete and incomplete Freund's adjuvant (CFA/IFA) is known to protect mice from atherosclerosis. This vaccination induces antigen-specific IgG1 and IgG2c antibody responses and a robust CD4 T cell response in lymph nodes. However, CFA/IFA cannot be used in humans. To find a clinically applicable adjuvant, we tested the effect of vaccinating Apoe-deficient mice with ApoB peptide P6 (TGAYSNASSTESASY). In a broad screening experiment, Addavax, a squalene oil similar to MF59, was the only adjuvant that showed similar efficacy as CFA/IFA. This was confirmed in a confirmation experiment for both the aortic arch and whole aorta analyzed by en face analysis after atherosclerotic lesion staining. Mechanistically, restimulated peritoneal cells from mice immunized with P6 in Addavax released significant amounts of IL-10. Unlike P6 in CFA/IFA, vaccination with P6 in Addavax did not induce any detectable IgG1 or IgG2c antibodies to P6. These data suggest that squalene-based adjuvants such as MF59 are good candidate adjuvants for developing a clinically effective atherosclerosis vaccine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. Complications following surgery and adjuvant irradiation in rectal carcinoma

    International Nuclear Information System (INIS)

    Suhr, P.; Limmer, J.

    1991-01-01

    Colorectal cancer is one of the most common human malignancies. Adjuvant irradiation can decrease the risk of recurrence and subsequently the associated morbidity compared with surgery alone. The rate of radiation-induced complications amounts to approximately 10%, which is substantially lower than the frequency of observed local failure. (orig.) [de

  13. 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

    Directory of Open Access Journals (Sweden)

    Annalisa eCiabattini

    2015-08-01

    Full Text Available 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 1821 adjuvants, administered by the parenteral and nasal routes. By 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 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 subcutaneous 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.

  14. Cellular Adjuvant Properties, Direct Cytotoxicity of Re-differentiated Vα24 Invariant NKT-like Cells from Human Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Shuichi Kitayama

    2016-02-01

    Full Text Available 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.

  15. Old and new adjuvants for hepatitis B vaccines.

    Science.gov (United States)

    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.

  16. Adjuvant chemotherapy for osteosarcoma.

    Science.gov (United States)

    Eilber, F R; Rosen, G

    1989-08-01

    present to minimally include high-dose methotrexate, Adriamycin, and cisplatin. It would also appear from several of these reports that not only is the adjuvant use of these chemotherapeutic agents indicated, but that the preoperative use of these agents has had significant advantages. The neoadjuvant chemotherapy begins the essential systemic chemotherapy at a very early stage, allows histologic assessment of treatment effect, permits altering drug regimens postoperative, and in many reported trials has allowed less than amputative surgery (limb salvage) to be performed. Finally, close follow-up of patients with osteosarcoma has therapeutic value.(ABSTRACT TRUNCATED AT 400 WORDS)

  17. Adjuvant chemotherapy and cancer cure

    International Nuclear Information System (INIS)

    Bertino, J.R.

    1983-01-01

    The use of chemotherapy as an adjuvant to surgery and/or radiotherapy is well founded in experimental tumor systems and appears to be effective in patients in some circumstances. It is clear from both clinical and experimental studies that (1) the dose is important, (2) the earlier chemotherapy is started after primary therapy the better, and (3) combination chemotherapy may be more effective than single-agent treatment. The better the estimation of risk of recurrence, the better the assessment of the risk-benefit ratio with adjuvant therapy. Salvage therapy as well as relative risk of recurrence are considerations in the choice of patients to be treated. Finally, some evidence is presented to indicate that alkylating agents may not be necessary in combination regimens for adjuvant therapy if effective antimetabolite combinations are available

  18. Chemokines as Cancer Vaccine Adjuvants

    Directory of Open Access Journals (Sweden)

    Agne Petrosiute

    2013-10-01

    Full Text Available 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.

  19. Physical exercise during adjuvant chemotherapy

    NARCIS (Netherlands)

    van Waart, H.

    2017-01-01

    This thesis evaluates the effect of physical exercise during chemotherapy. In chapter two the study design, rationale and methods of the Physical exercise during Adjuvant Chemotherapy Study (PACES) are described. Chapter three presents the effects of the randomized controlled trial evaluating a

  20. Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund’s adjuvant-induced knee arthritis

    Science.gov (United States)

    Robledo-González, LE; Martínez-Martínez, A; Vargas-Muñoz, VM; Acosta-González, RI; Plancarte-Sánchez, R; Anaya-Reyes, M; Fernández del Valle-Laisequilla, C; Reyes-García, JG; Jiménez-Andrade, JM

    2017-01-01

    Background The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the anti-nociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund’s adjuvant (CFA)-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined. Methods Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding) and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p.) administered dose of mazindol was given (1, 3 and 10 mg/kg). Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15–day 26) was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro-computed tomography. Results Acute administration of mazindol decreased the spontaneous pain-like behaviors in a dose-dependent manner without reducing the knee edema. However, mazindol at 10 mg/kg significantly increased the locomotor activity; therefore, 3 mg/kg mazindol was used for further studies. Repeated administration of 3 mg/kg mazindol significantly decreased the pain-like behaviors without modifying locomotor activity. The antinociceptive effect of mazindol was blocked by administration of a D2-like receptor antagonist (haloperidol), but not by administration of D1-like receptor antagonist (SCH 23390) or an opioid receptor antagonist (naloxone). Repeated administration of mazindol did not significantly modify the density and microarchitecture of periarticular bone of the arthritic

  1. Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus.

    Directory of Open Access Journals (Sweden)

    Mallika Sastry

    Full Text Available Appropriate adjuvant selection may be essential to optimize the potency and to tailor the immune response of subunit vaccines. To induce protective responses against respiratory syncytial virus (RSV-a highly prevalent childhood pathogen without a licensed vaccine-we previously engineered a pre-fusion-stabilized trimeric RSV F (pre-F "DS-Cav1" immunogen, which induced high titer RSV-neutralizing antibodies, in mice and non-human primates, when formulated with adjuvants Poly (I:C and Poly (IC:LC, respectively. To assess the impact of different adjuvants, here we formulated RSV F DS-Cav1 with multiple adjuvants and assessed immune responses. Very high RSV-neutralizing antibody responses (19,006 EC50 were observed in naïve mice immunized with 2 doses of DS-Cav1 adjuvanted with Sigma adjuvant system (SAS, an oil-in-water adjuvant, plus Carbopol; high responses (3658-7108 were observed with DS-Cav1 adjuvanted with Alum, SAS alone, Adjuplex, Poly (I:C and Poly (IC:LC; and moderate responses (1251-2129 were observed with DS-Cav1 adjuvanted with the TLR4 agonist MPLA, Alum plus MPLA or AddaVax. In contrast, DS-Cav1 without adjuvant induced low-level responses (6. A balanced IgG1 and IgG2a (Th2/Th1 immune response was elicited in most of the high to very high response groups (all but Alum and Adjuplex. We also tested the immune response induced by DS-Cav1 in elderly mice with pre-existing DS-Cav1 immunity; we observed that DS-Cav1 adjuvanted with SAS plus Carbopol boosted the response 2-3-fold, whereas DS-Cav1 adjuvanted with alum boosted the response 5-fold. Finally, we tested whether a mixture of ISA 71 VG and Carbopol would enhanced the antibody response in DS-Cav1 immunized calves. While pre-F-stabilized bovine RSV F induced very high titers in mice when adjuvanted with SAS plus Carbopol, the addition of Carbopol to ISA 71 VG did not enhance immune responses in calves. The vaccine response to pre-F-stabilized RSV F is augmented by adjuvant, but the

  2. Modern Vaccines/Adjuvants Formulation--Session 2 (Plenary II): May 15-17, 2013--Lausanne, Switzerland.

    Science.gov (United States)

    Collin, Nicolas

    2013-09-01

    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.

  3. Induction of CD8+ T-cell responses against subunit antigens by the novel cationic liposomal CAF09 adjuvant

    DEFF Research Database (Denmark)

    Korsholm, Karen Smith; Hansen, Jon; Karlsen, Kasper

    2014-01-01

    previously described CTL-inducing adjuvants, CAF05 (DDA/trehalose dibehenate (TDB)/Poly(I:C)), Aluminium/monophosphoryl lipid-A (MPL) and Montanide/CpG/IL-2. The optimal effect was obtained when the CAF09-adjuvanted vaccine was administered by the i.p. route, whereas s.c. administration primed limited CD8+ T...

  4. Adjuvant bisphosphonates in early breast cancer

    DEFF Research Database (Denmark)

    Hadji, P; Coleman, R E; Wilson, C

    2016-01-01

    Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have...... regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature...... was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus...

  5. Opioid adjuvant strategy: improving opioid effectiveness.

    Science.gov (United States)

    Bihel, Frédéric

    2016-01-01

    Opioid analgesics continue to be the mainstay of pharmacologic treatment of moderate to severe pain. Many patients, particularly those suffering from chronic pain, require chronic high-dose analgesic therapy. Achieving clinical efficacy and tolerability of such treatment regimens is hampered by the appearance of opioid-induced side effects such as tolerance, hyperalgesia and withdrawal syndrome. Among the therapeutic options to improve the opioid effectiveness, this current review focuses on strategies combining opioids to other drugs that can modulate opioid-mediated effects. We will discuss about experimental evidences reported for several potential opioid adjuvants, including N-methyl-D-aspartate receptor antagonists, 5-HT7 agonists, sigma-1 antagonists, I2-R ligands, cholecystokinin antagonists, neuropeptide FF-R antagonists and toll-like receptor 4 antagonists.

  6. Antibody-antigen-adjuvant conjugates enable co-delivery of antigen and adjuvant to dendritic cells in cis but only have partial targeting specificity.

    Directory of Open Access Journals (Sweden)

    Martin Kreutz

    Full Text Available Antibody-antigen conjugates, which promote antigen-presentation by dendritic cells (DC by means of targeted delivery of antigen to particular DC subsets, represent a powerful vaccination approach. To ensure immunity rather than tolerance induction the co-administration of a suitable adjuvant is paramount. However, co-administration of unlinked adjuvant cannot ensure that all cells targeted by the antibody conjugates are appropriately activated. Furthermore, antigen-presenting cells (APC that do not present the desired antigen are equally strongly activated and could prime undesired responses against self-antigens. We, therefore, were interested in exploring targeted co-delivery of antigen and adjuvant in cis in form of antibody-antigen-adjuvant conjugates for the induction of anti-tumour immunity. In this study, we report on the assembly and characterization of conjugates consisting of DEC205-specific antibody, the model antigen ovalbumin (OVA and CpG oligodeoxynucleotides (ODN. We show that such conjugates are more potent at inducing cytotoxic T lymphocyte (CTL responses than control conjugates mixed with soluble CpG. However, our study also reveals that the nucleic acid moiety of such antibody-antigen-adjuvant conjugates alters their binding and uptake and allows delivery of the antigen and the adjuvant to cells partially independently of DEC205. Nevertheless, antibody-antigen-adjuvant conjugates are superior to antibody-free antigen-adjuvant conjugates in priming CTL responses and efficiently induce anti-tumour immunity in the murine B16 pseudo-metastasis model. A better understanding of the role of the antibody moiety is required to inform future conjugate vaccination strategies for efficient induction of anti-tumour responses.

  7. Effect of adjuvants on responses to skin immunization by microneedles coated with influenza subunit vaccine.

    Directory of Open Access Journals (Sweden)

    William C Weldon

    Full Text Available Recent studies have demonstrated the effectiveness of vaccine delivery to the skin by vaccine-coated microneedles; however there is little information on the effects of adjuvants using this approach for vaccination. Here we investigate the use of TLR ligands as adjuvants with skin-based delivery of influenza subunit vaccine. BALB/c mice received 1 µg of monovalent H1N1 subunit vaccine alone or with 1 µg of imiquimod or poly(I:C individually or in combination via coated microneedle patches inserted into the skin. Poly(I:C adjuvanted subunit influenza vaccine induced similar antigen-specific immune responses compared to vaccine alone when delivered to the skin by microneedles. However, imiquimod-adjuvanted vaccine elicited higher levels of serum IgG2a antibodies and increased hemagglutination inhibition titers compared to vaccine alone, suggesting enhanced induction of functional antibodies. In addition, imiquimod-adjuvanted vaccine induced a robust IFN-γ cellular response. These responses correlated with improved protection compared to influenza subunit vaccine alone, as well as reduced viral replication and production of pro-inflammatory cytokines in the lungs. The finding that microneedle delivery of imiquimod with influenza subunit vaccine induces improved immune responses compared to vaccine alone supports the use of TLR7 ligands as adjuvants for skin-based influenza vaccines.

  8. GLA-AF, an emulsion-free vaccine adjuvant for pandemic influenza.

    Science.gov (United States)

    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.

  9. Self-Adjuvanting Glycopeptide Conjugate Vaccine against Disseminated Candidiasis

    Science.gov (United States)

    Xin, Hong; Cartmell, Jonathan; Bailey, Justin J.; Dziadek, Sebastian; Bundle, David R.; Cutler, Jim E.

    2012-01-01

    Our research on pathogenesis of disseminated candidiasis led to the discovery that antibodies specific for Candida albicans cell surface β-1, 2–mannotriose [β-(Man)3] protect mice. A 14 mer peptide Fba, which derived from the N-terminal portion of the C. albicans cytosolic/cell surface protein fructose-bisphosphate aldolase, was used as the glycan carrier and resulted in a novel synthetic glycopeptide vaccine β-(Man)3-Fba. By a dendritic cell-based immunization approach, this conjugate induced protective antibody responses against both the glycan and peptide parts of the vaccine. In this report, we modified the β-(Man)3-Fba conjugate by coupling it to tetanus toxoid (TT) in order to improve immunogenicity and allow for use of an adjuvant suitable for human use. By new immunization procedures entirely compatible with human use, the modified β-(Man)3-Fba-TT was administered either alone or as a mixture made with alum or monophosphoryl lipid A (MPL) adjuvants and given to mice by a subcutaneous (s.c.) route. Mice vaccinated with or, surprisingly, without adjuvant responded well by making robust antibody responses. The immunized groups showed a high degree of protection against a lethal challenge with C. albicans as evidenced by increased survival times and reduced kidney fungal burden as compared to control groups that received only adjuvant or DPBS buffer prior to challenge. To confirm that induced antibodies were protective, sera from mice immunized against the β-(Man)3-Fba-TT conjugate transferred protection against disseminated candidiasis to naïve mice, whereas C. albicans-absorbed immune sera did not. Similar antibody responses and protection induced by the β-(Man)3-Fba-TT vaccine was observed in inbred BALB/c and outbred Swiss Webster mice. We conclude that addition of TT to the glycopeptide conjugate results in a self-adjuvanting vaccine that promotes robust antibody responses without the need for additional adjuvant, which is novel and represents a

  10. Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund’s adjuvant-induced knee arthritis

    Directory of Open Access Journals (Sweden)

    Robledo-González LE

    2017-07-01

    Full Text Available LE Robledo-González,1 A Martínez-Martínez,1 VM Vargas-Muñoz,1 RI Acosta-González,2 R Plancarte-Sánchez,3 M Anaya-Reyes,4 C Fernández del Valle-Laisequilla,5 JG Reyes-García,6 JM Jiménez-Andrade1 1Laboratorio de Farmacología, 2Departamento de Análisis Clínicos, Unidad Académica Multidisciplinaria Reynosa-Aztlán, UAT, Reynosa, Tamaulipas, Mexico; 3Departamento de Anestesiología, Terapia Intensiva y Clínica del Dolor, Instituto Nacional de Cancerología, Mexico City, Mexico; 4Investigación Clínica y Farmacovigilancia, 5Investigación Clínica y Farmacovigilancia, Productos Medix, S.A. de C.V., Mexico City, Mexico; 6Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico Background: The role of dopaminergic system in the development of rheumatoid arthritis-related pain, a major symptom in this disease, has not been explored. Therefore, the antinociceptive effect of mazindol, a dopamine uptake inhibitor, was evaluated in a model of complete Freund’s adjuvant (CFA-induced arthritis. Furthermore, as studies have shown that the dopaminergic system regulates bone metabolism, the effect of mazindol on bone mass and microarchitecture was determined.Methods: Adult ICR male mice received intra-articular injections of either CFA or saline into the right knee joint every week. Spontaneous pain-like behaviors (flinching and guarding and locomotor activity were assessed at day 26 post-first CFA, following which, a single intraperitoneally (i.p. administered dose of mazindol was given (1, 3 and 10 mg/kg. Then, the antinociceptive effect of a repeated administration of 3 mg/kg mazindol (daily, i.p.; day 15–day 26 was evaluated. Additionally, at day 26, the participation of D1-like, D2-like or opioid receptors in the antinociceptive effect of mazindol was evaluated. The effect of mazindol on bone density and microarchitecture was evaluated by micro

  11. Role of Respirable Saudi Arabian Sand and Pyridostigmine in the Gulf War syndrome: An Autoimmune Adjuvant Disease

    National Research Council Canada - National Science Library

    Sopori, Mohan

    2002-01-01

    In the Lewis rat, inhalation of silica (SL) in realistic doses for 6 wk exacerbated the Mycobacterium- induced autoimmune adjuvant disease and impaired the humoral as well as cellular immune responses...

  12. Elucidating the mechanisms of protein antigen adsorption to the CAF/NAF liposomal vaccine adjuvant systems

    DEFF Research Database (Denmark)

    Hamborg, Mette; Rose, Fabrice; Jorgensen, Lene

    2014-01-01

    is generally known about how antigens and adjuvants interact at the molecular level. The aim of this study was to elucidate the mechanisms of interactions between the equally sized, but oppositely charged model protein antigens α-lactalbumin and lysozyme, and i) the clinically tested cationic liposomal...... antigens are presented to antigen-presenting cells, and may play an important role for the efficacy of the vaccine-induced immune response. These studies thus exemplify the importance of characterizing the molecular interactions between the vaccine antigen and adjuvant along with immunogenicity......The reverse vaccinology approach has recently resulted in the identification of promising protein antigens, which in combination with appropriate adjuvants can stimulate customized, protective immune responses. Although antigen adsorption to adjuvants influences vaccine efficacy and safety, little...

  13. Novel Adjuvants and Immunomodulators for Veterinary Vaccines

    DEFF Research Database (Denmark)

    Heegaard, Peter M. H.; Fang, Yongxiang; Jungersen, Gregers

    2016-01-01

    Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the va...

  14. House dust extracts contain potent immunological adjuvants

    NARCIS (Netherlands)

    Beukelman, C.J.; Dijk, H. van; Aerts, P.C.; Rademaker, P.M.; Berrens, L.; Willers, J.M.N.

    1987-01-01

    A crude aqueous extract of house dust and two house dust subfractions were tested for adjuvant activity in a sensitivity assay performed in mice. Evidence is presented that house dust contains at least two potent immunological adjuvants. One of these, present in both subfractions, was probably

  15. Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy.

    Science.gov (United States)

    Arriagada, R; Lê, M G; Spielmann, M; Mauriac, L; Bonneterre, J; Namer, M; Delozier, T; Hill, C; Tursz, T

    2005-03-01

    The aim of this multicenter trial was to evaluate the role of ovarian suppression in patients with early breast cancer previously treated with local surgery and adjuvant chemotherapy. Nine hundred and twenty-six premenopausal patients with completely resected breast cancer and either axillary node involvement or histological grade 2 or 3 tumors were randomized after surgery to adjuvant chemotherapy alone (control arm) or adjuvant chemotherapy plus ovarian suppression (ovarian suppression arm). Ovarian suppression was obtained by either radiation-induced ovarian ablation or triptorelin for 3 years. The analyses were performed with Cox models stratified by center. Median follow-up was 9.5 years. Mean age was 43 years. Ninety per cent of patients had histologically proven positive axillary nodes, 63% positive hormonal receptors and 77% had received an anthracycline-based chemotherapy regimen. Ovarian suppression was by radiation-induced ovarian ablation (45% of patients) or with triptorelin (48%). At the time of randomization, all patients had regular menses or their follicle-stimulating hormone and estradiol levels indicated a premenopausal status. The 10-year disease-free survival rates were 49% [95% confidence interval (CI) 44% to 54%] in both arms (P = 0.51). The 10-year overall survival rates were 66% (95% CI 61% to 70%) for the ovarian suppression arm and 68% (95% CI 63% to 73%) for the control arm (P = 0.19). There were no variations in the treatment effect according to age, hormonal receptor status or ovarian suppression modality. However, in patients suppression significantly decreased the risk of recurrence (P = 0.01). The results of this trial, after at least 10 years of follow-up, do not favor the use of ovarian suppression after adjuvant chemotherapy. The potential beneficial effect in younger women with hormono-dependent tumors should be further assessed.

  16. Adjuvants are key factors for the development of future vaccines: Lessons from the Finlay Adjuvant platform

    Directory of Open Access Journals (Sweden)

    Oliver ePérez

    2013-12-01

    Full Text Available The development of effective vaccines against neglected diseases, especially those associated with poverty and social deprivation, is urgently needed. Modern vaccine technologies and a better understanding of the immune response have provided scientists with the tools for rational and safer design of subunit vaccines. Often, however, subunit vaccines do not elicit strong immune responses, highlighting the need to incorporate better adjuvants; this step therefore becomes a key factor for vaccine development. In this review we outline some key features of modern vaccinology that are linked with the development of better adjuvants. In line with the increased desire to obtain novel adjuvants for future vaccines, the Finlay Adjuvant Platform offers a novel approach for the development of new and effective adjuvants. The Finlay Adjuvants (AFs, AFPL (proteoliposome and AFCo (cochleate, were initially designed for parenteral and mucosal applications, and constitute potent adjuvants for the induction of Th1 responses against several antigens. This review summarizes the status of the Finlay technology in producing promising adjuvants for unsolved-vaccine diseases including mucosal approaches and therapeutic vaccines. Ideas related to adjuvant classification, adjuvant selection, and their possible influence on innate recognition via multiple toll-like receptors are also discussed.

  17. Influence of various forms of dialyzable leukocyte extracts on rat adjuvant arthritis

    International Nuclear Information System (INIS)

    Stancikova, Maria; Rovensky, Jozef; Blazickova, Stanislava; Pekarek, J.; Cech, Karel

    1994-01-01

    Adjuvant-induced arthritis in rats is a chronic inflammatory disease, widely as an animal model for rheumatoid arthritis. In our study the effect of various fractions of dialyzable leukocyte extract (DLE): DLE I-molecular weight below 10 kDa (commercial preparation), DLE II-molecular weight below 5 kDa (suppressor fraction), DLE III-molecular weight 5-10 kDa on rat adjuvant-induced arthritis was studied. The adjuvant arthritic (AA) rats were treated with DLE fractions i.p. in solutions containing an active substance isolated from 12.5 x 10 6 and 6.25 x 10 6 leukocytes from day 1 (adjuvant injected) through day 18, every second day (total 9 times). Various markers in inflammation, immune function and joint destruction were evaluated: hind paw volume, serum hyaluronic acid, serum albumin and biopterin in urine. All these markers showed a significant improvement after using fraction DLE II in comparison with AA controls. Fractions DLE I and DLE III influenced only some markers of inflammation and immune function. Our results demonstrated a therapeutical effect of fraction DLE II on rat adjuvant-induced arthritis. (author). 22 refs, 2 figs, 2 tabs

  18. Intranasal Immunization Using Mannatide as a Novel Adjuvant for an Inactivated Influenza Vaccine and Its Adjuvant Effect Compared with MF59.

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    Shu-Ting Ren

    Full Text Available Intranasal vaccination is more potent than parenteral injection for the prevention of influenza. However, because the poor efficiency of antigen uptake across the nasal mucosa is a key issue, immunostimulatory adjuvants are essential for intranasal vaccines. The immunomodulator mannatide or polyactin (PA has been used for the clinical treatment of impaired immunity in China, but its adjuvant effect on an inactivated trivalent influenza vaccine (ITIV via intranasal vaccination is unclear. To explore the adjuvant effect of PA, an inactivated trivalent influenza virus with or without PA or MF59 was instilled intranasally once a week in BALB/c mice. Humoral immunity was assessed by both the ELISA and hemagglutination inhibition (HI methods using antigen-specific antibodies. Splenic lymphocyte proliferation and the IFN-γ level were measured to evaluate cell-mediated immunity. The post-vaccination serum HI antibody geometric mean titers (GMTs for the H1N1 and H3N2 strains, antigen-specific serum IgG and IgA GMTs, mucosal SIgA GMT, splenic lymphocyte proliferation, and IFN-γ were significantly increased in the high-dose PA-adjuvanted vaccine group. The seroconversion rate and the mucosal response for the H3N2 strain were significantly elevated after high-dose PA administration. These adjuvant effects of high-dose PA for the influenza vaccine were comparable with those of the MF59 adjuvant, and abnormal signs or pathological changes were not found in the evaluated organs. In conclusion, PA is a novel mucosal adjuvant for intranasal vaccination with the ITIV that has safe and effective mucosal adjuvanticity in mice and successfully induces both serum and mucosal antibody responses and a cell-mediated response.

  19. Cyclic GMP-AMP displays mucosal adjuvant activity in mice.

    Directory of Open Access Journals (Sweden)

    Ivana Škrnjug

    Full Text Available The recently discovered mammalian enzyme cyclic GMP-AMP synthase produces cyclic GMP-AMP (cGAMP after being activated by pathogen-derived cytosolic double stranded DNA. The product can stimulate STING-dependent interferon type I signaling. Here, we explore the efficacy of cGAMP as a mucosal adjuvant in mice. We show that cGAMP can enhance the adaptive immune response to the model antigen ovalbumin. It promotes antigen specific IgG and a balanced Th1/Th2 lymphocyte response in immunized mice. A characteristic of the cGAMP-induced immune response is the slightly reduced induction of interleukin-17 as a hallmark of Th17 activity--a distinct feature that is not observed with other cyclic di-nucleotide adjuvants. We further characterize the innate immune stimulation activity in vitro on murine bone marrow-derived dendritic cells and human dendritic cells. The observed results suggest the consideration of cGAMP as a candidate mucosal adjuvant for human vaccines.

  20. Cyclic GMP-AMP displays mucosal adjuvant activity in mice.

    Science.gov (United States)

    Škrnjug, Ivana; Guzmán, Carlos Alberto; Rueckert, Christine; Ruecker, Christine

    2014-01-01

    The recently discovered mammalian enzyme cyclic GMP-AMP synthase produces cyclic GMP-AMP (cGAMP) after being activated by pathogen-derived cytosolic double stranded DNA. The product can stimulate STING-dependent interferon type I signaling. Here, we explore the efficacy of cGAMP as a mucosal adjuvant in mice. We show that cGAMP can enhance the adaptive immune response to the model antigen ovalbumin. It promotes antigen specific IgG and a balanced Th1/Th2 lymphocyte response in immunized mice. A characteristic of the cGAMP-induced immune response is the slightly reduced induction of interleukin-17 as a hallmark of Th17 activity--a distinct feature that is not observed with other cyclic di-nucleotide adjuvants. We further characterize the innate immune stimulation activity in vitro on murine bone marrow-derived dendritic cells and human dendritic cells. The observed results suggest the consideration of cGAMP as a candidate mucosal adjuvant for human vaccines.

  1. Tocotrienols are good adjuvants for developing cancer vaccines

    International Nuclear Information System (INIS)

    Abdul Hafid, Sitti Rahma; Radhakrishnan, Ammu Kutty; Nesaretnam, Kalanithi

    2010-01-01

    Dendritic cells (DCs) have the potential for cancer immunotherapy due to their ability to process and present antigens to T-cells and also in stimulating immune responses. However, DC-based vaccines have only exhibited minimal effectiveness against established tumours in mice and humans. The use of appropriate adjuvant enhances the efficacy of DC based cancer vaccines in treating tumours. In this study we have used tocotrienol-rich fraction (TRF), a non-toxic natural compound, as an adjuvant to enhance the effectiveness of DC vaccines in treating mouse mammary cancers. In the mouse model, six-week-old female BALB/c mice were injected subcutaneously with DC and supplemented with oral TRF daily (DC+TRF) and DC pulsed with tumour lysate from 4T1 cells (DC+TL). Experimental mice were also injected with DC pulsed with tumour lysate and supplemented daily with oral TRF (DC+TL+TRF) while two groups of animal which were supplemented daily with carrier oil (control) and with TRF (TRF). After three times vaccination, mice were inoculated with 4T1 cells in the mammary breast pad to induce tumour. Our study showed that TRF in combination with DC pulsed with tumour lysate (DC+TL+TRF) injected subcutaneously significantly inhibited the growth of 4T1 mammary tumour cells as compared to control group. Analysis of cytokines production from murine splenocytes showed significant increased productions of IFN-γ and IL-12 in experimental mice (DC+TL+TRF) compared to control, mice injected with DC without TRF, mice injected with DC pulsed with tumour lysate and mice supplemented with TRF alone. Higher numbers of cytotoxic T cells (CD8) and natural killer cells (NK) were observed in the peripheral blood of TRF adjuvanted DC pulsed tumour lysate mice. Our study show that TRF has the potential to be an adjuvant to augment DC based immunotherapy

  2. Tocotrienols are good adjuvants for developing cancer vaccines

    Directory of Open Access Journals (Sweden)

    Radhakrishnan Ammu

    2010-01-01

    Full Text Available Abstract Background Dendritic cells (DCs have the potential for cancer immunotherapy due to their ability to process and present antigens to T-cells and also in stimulating immune responses. However, DC-based vaccines have only exhibited minimal effectiveness against established tumours in mice and humans. The use of appropriate adjuvant enhances the efficacy of DC based cancer vaccines in treating tumours. Methods In this study we have used tocotrienol-rich fraction (TRF, a non-toxic natural compound, as an adjuvant to enhance the effectiveness of DC vaccines in treating mouse mammary cancers. In the mouse model, six-week-old female BALB/c mice were injected subcutaneously with DC and supplemented with oral TRF daily (DC+TRF and DC pulsed with tumour lysate from 4T1 cells (DC+TL. Experimental mice were also injected with DC pulsed with tumour lysate and supplemented daily with oral TRF (DC+TL+TRF while two groups of animal which were supplemented daily with carrier oil (control and with TRF (TRF. After three times vaccination, mice were inoculated with 4T1 cells in the mammary breast pad to induce tumour. Results Our study showed that TRF in combination with DC pulsed with tumour lysate (DC+TL+TRF injected subcutaneously significantly inhibited the growth of 4T1 mammary tumour cells as compared to control group. Analysis of cytokines production from murine splenocytes showed significant increased productions of IFN-γ and IL-12 in experimental mice (DC+TL+TRF compared to control, mice injected with DC without TRF, mice injected with DC pulsed with tumour lysate and mice supplemented with TRF alone. Higher numbers of cytotoxic T cells (CD8 and natural killer cells (NK were observed in the peripheral blood of TRF adjuvanted DC pulsed tumour lysate mice. Conclusion Our study show that TRF has the potential to be an adjuvant to augment DC based immunotherapy.

  3. The identification of plant lectins with mucosal adjuvant activity

    Science.gov (United States)

    Lavelle, E C; Grant, G; Pusztai, A; Pfüller, U; O'hagan, D T

    2001-01-01

    To date, the most potent mucosal vaccine adjuvants to be identified have been bacterial toxins. The present data demonstrate that the type 2 ribosome-inactivating protein (type 2 RIP), mistletoe lectin I (ML-I) is a strong mucosal adjuvant of plant origin. A number of plant lectins were investigated as intranasal (i.n.) coadjuvants for a bystander protein, ovalbumin (OVA). As a positive control, a potent mucosal adjuvant, cholera toxin (CT), was used. Co-administration of ML-I or CT with OVA stimulated high titres of OVA-specific serum immunoglobulin G (IgG) in addition to OVA-specific IgA in mucosal secretions. CT and ML-I were also strongly immunogenic, inducing high titres of specific serum IgG and specific IgA at mucosal sites. None of the other plant lectins investigated significantly boosted the response to co-administered OVA. Immunization with phytohaemagglutinin (PHA) plus OVA elicited a lectin-specific response but did not stimulate an enhanced response to OVA compared with the antigen alone. Intranasal delivery of tomato lectin (LEA) elicited a strong lectin-specific systemic and mucosal antibody response but only weakly potentiated the response to co-delivered OVA. In contrast, administration of wheatgerm agglutinin (WGA) or Ulex europaeus lectin 1 (UEA-I) with OVA stimulated a serum IgG response to OVA while the lectin-specific responses (particularly for WGA) were relatively low. Thus, there was not a direct correlation between immunogenicity and adjuvanticity although the strongest adjuvants (CT, ML-I) were also highly immunogenic. PMID:11168640

  4. Development of sensitisation or tolerance following repeated OVA inhalation in BALB/cJ mice. Dose-dependency and modulation by the Al(OH)3 adjuvant

    DEFF Research Database (Denmark)

    Clausen, Susanne Knoth; Bergqvist, Mette; Poulsen, Lars K.

    2003-01-01

    Anthropogenically induced exposures may, due to their adjuvant effect, promote development of sensitisation to commonly occurring aeroallergens. No generally accepted model exists for determination of adjuvant effect of airborne substances. Therefore, BALB/cJ mice were exposed for 10 consecutive...

  5. [The effect of aluminum adjuvant and immunization schedule on immunogenicity of Sabin inactivated poliovirus vaccine].

    Science.gov (United States)

    Wang, Fang; Zhang, Ming; Xie, Bing-Feng; Cao, Han; Tong, Shao-Yong; Wang, Jun-Rong; Yu, Xiao-Ping; Tang, Yang; Yang, Jing-Ran; Sun, Ming-Bo

    2013-04-01

    To study the effect of aluminume adjuvant and immunization schedule on immunogenicity of Sabin inactivated poliovirus vaccine. Four batches of Sabin IPV were produced by different concentrations of type 1, 2, and 3 poliovirus and administrated on three-dose schedule at 0, 1, 2 months and 0, 2, 4 months on rats. Serum samples were collected one month after each dose and neutralizing antibody titers against three types poliovirus were determined by micro-neutralization assay. The GMTs of neutralizing antibodies against three types poliovirus increased significantly and the seropositivity rates were 100% in all groups after 3 doses. There was no significant difference between two immunization schedules, and the 0, 2, 4 month schedule could induce higher level neutralizing antibody compared to the 0, 1, 2 month schedule. The groups with aluminum adjuvant could induce higher level neutralizing antibody compared to the groups without adjuvant. Aluminum djuvant and immunization schedule could improve the immunogenicity of Sabin IPV.

  6. Extended Adjuvant Therapy for Breast Cancer

    Science.gov (United States)

    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.

  7. CpG-DNA enhancement the immune elicited as adjuvant of foot- and- mouth disease vaccine

    Directory of Open Access Journals (Sweden)

    Morshedi, A.

    2010-01-01

    Full Text Available In the present study the effect of the locally produced genetic adjuvant of ginea pig specific CpG-motif-containing oligodeoxynucleotide (CpG-ODN in an inactivated FMD virus vaccine was evaluated. Boosting the ginea pigs with FMD vaccine along with CpG-ODN adjuvant produced relatively higher ratio (5-fold of FMDV-specific IgG2a / IgG1 than those vaccinated in the absence of CpG-ODN. The neutralizing antibody (NA titer induced by FMD vaccine along with CpG-ODN adjuvant was significantly higher (8-fold than NA titer induced by the classical FMD vaccine in Alum adjuvant. The titer of NA and virus clearance from serum was consistently and significantly higher in animals primed with FMD vaccine and boosted by CpG-ODN than the classical FMD vaccine. The results of this study showed the potential of CpG-ODN as a genetic adjuvant to FMD vaccine in the development of Th1 responses.

  8. Effects of adjuvants on IgG subclasses elicited by virus-like Particles

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    Visciano Maria Luisa

    2012-01-01

    Full Text Available Abstract Background Virus-Like Particles (VLPs represent an efficient strategy to present and deliver conformational antigens to the immune system, inducing both arms of the adaptive immune response. Moreover, their particulate structure surrounded by cell membrane provides an adjuvanted effect to VLP-based immunizations. In the present study, the elicitation of different patterns of IgG subclasses by VLPs, administered in CpG ODN1826 or poly(I:C adjuvants, has been evaluated in an animal model. Results Adjuvanted VLPs elicited a higher titer of total specific IgG compared to VLPs alone. Furthermore, while VLPs alone induced a balanced TH2 pattern, VLPs formulated with either adjuvant elicited a TH1-biased IgG subclasses (IgG2a and IgG3, with poly(I:C more potent than CpG ODN1826. Conclusions The results confirmed that adjuvants efficiently improve antigen immunogenicity and represent a suitable strategy to skew the adaptive immune response toward the differentiation of the desired T helper subset, also using VLPs as antigen.

  9. Adjuvant chemo- and radiotherapy in gastrointestinal tumors

    International Nuclear Information System (INIS)

    Sendler, A.; Feldmann, H.J.; Fink, U.; Molls, M.; Siewert, J.R.

    1995-01-01

    In modern surgical oncology, adjuvant therapies are important complementary strategies. In local advanced carcinomas of the gastrointestinal tract, 5-year survival data are still disappointing despite standardized surgery. In this context, it has to be differentiated between adjuvant therapy following complete tumor exstirpation (so-called UICC R 0 resection) and additive therapies following incomplete tumor resections (UICC R 1 or R 2 resection). Modalities in the adjuvant setting are chemotherapy, radiotherapy or the combined radio-/chemotherapy. In esophageal and gastric cancer there is up to now no benefit of postoperative adjuvant therapy. In pancreatic cancer, there are studies indicating a benefit of combined radio-/chemotherapy after complete tumor resection. A standard adjuvant chemotherapeutic treatment is proven in colon cancer stage III (Dukes C) with levamisole and 5-FU. Completely resected rectal carcinoma should be treated postoperatively with combined radio-/chemotherapy. In the common clinical or practical setting, adjuvant therapy is indicated only in locally advanced gastrointestinal tumors following R 0 resection. Postoperative therapy following incomplete tumor resection has its reason only in a palliative intention. (orig.) [de

  10. Applications of nanomaterials as vaccine adjuvants

    Science.gov (United States)

    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

  11. Adjuvant chemoradiotherapy in gastric cancer

    International Nuclear Information System (INIS)

    Gonzalez Herrera, Ileana

    2002-01-01

    The main objetives of this work are to determine the tolerability of the adjuvant chemo-radiotherapy's treatment in Costa Rican patients in the Hospital San Juan de Dios, as well as to value the toxicity's level presented. A bibliographic review is realized to justify the use of this treatment's type and to determine the feasibility of its performance with the different services that are involved. The treatment's plan consisted on: after an undergoing of a gastrectomy, the patients were appointed to receive post-operative treatment combined of 5-F U plus leucovorin and radiation. The fluoracil was injected intravenous in continue infusion. The obtained results prove that the use of a lineal accelerator must be recommended as a standard treatment for this pathology by the region to treat and the complexity of the fields. The ganglion dissection performed with more frequency is inferior to one D 2, and the treatment with radiotherapy cobalt 60 and infusion al 5-F U is well tolerated with moderate-light toxicity and easily manageable [es

  12. Enhanced pulmonary immunization with aerosolized inactivated influenza vaccine containing delta inulin adjuvant.

    Science.gov (United States)

    Murugappan, Senthil; Frijlink, Henderik W; Petrovsky, Nikolai; Hinrichs, Wouter L J

    2015-01-23

    Vaccination is the primary intervention to contain influenza virus spread during seasonal and pandemic outbreaks. Pulmonary vaccination is gaining increasing attention for its ability to induce both local mucosal and systemic immune responses without the need for invasive injections. However, pulmonary administration of whole inactivated influenza virus (WIV) vaccine induces a Th2 dominant systemic immune response while a more balanced Th1/Th2 vaccine response may be preferred and only induces modest nasal immunity. This study evaluated immunity elicited by pulmonary versus intramuscular (i.m.) delivery of WIV, and tested whether the immune response could be improved by co-administration of delta (δ)-inulin, a novel carbohydrate-based particulate adjuvant. After pulmonary administration both unadjuvanted and δ-inulin adjuvanted WIV induced a potent systemic immune response, inducing higher serum anti-influenza IgG titers and nasal IgA titers than i.m. administration. Moreover, the addition of δ-inulin induced a more balanced Th1/Th2 response and induced higher nasal IgA titers versus pulmonary WIV alone. Pulmonary WIV alone or with δ-inulin induced hemagglutination inhibition (HI) titers>40, titers which are considered protective against influenza virus. In conclusion, in this study we have shown that δ-inulin adjuvanted WIV induces a better immune response after pulmonary administration than vaccine alone. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. A New Adjuvant Combined with Inactivated Influenza Enhances Specific CD8 T Cell Response in Mice and Decreases Symptoms in Swine Upon Challenge.

    Science.gov (United States)

    Bouguyon, Edwige; Goncalves, Elodie; Shevtsov, Alexander; Maisonnasse, Pauline; Remyga, Stepan; Goryushev, Oleg; Deville, Sebastien; Bertho, Nicolas; Ben Arous, Juliette

    2015-11-01

    Vaccination is the most effective way to control swine influenza virus (SIV) in the field. Classical vaccines are based on inactivated antigens formulated with an oil emulsion or a polymeric adjuvant. Standard adjuvants enhance the humoral response and orient the immune response toward a Th2 response. An important issue is that current vaccines do not protect against new strains. One approach to improve cross-protection is to enhance Th1 and cytotoxic responses. The development of adjuvants orienting the immune response of inactivated vaccines toward Th1/Cytotoxic responses would be highly beneficial. This study shows that the water in oil in water emulsion adjuvant Montanide™ ISA 201 VG allows the induction of anti-influenza CD8 T cell in mice and induces homologous protection against an H1N1 challenge in swine. Such adjuvants that induce both humoral and cell-mediated immunity could improve the protection conferred by SIV vaccines in the field.

  14. Structural perturbation of diphtheria toxoid upon adsorption to aluminium hydroxide adjuvant

    NARCIS (Netherlands)

    Regnier, M.; Metz, B.; Tilstra, W.; Hendriksen, C.; Jiskoot, W.; Norde, W.; Kersten, G.

    2012-01-01

    Aluminium-containing adjuvants are often used to enhance the potency of vaccines. In the present work we studied whether adsorption of diphtheria toxoid to colloidal aluminium hydroxide induces conformational changes of the antigen. Diphtheria toxoid has a high affinity for the aluminium hydroxide

  15. Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant

    NARCIS (Netherlands)

    Overwijk, Willem W.; de Visser, Karin E.; Tirion, Felicia H.; de Jong, Laurina A.; Pols, Thijs W. H.; van der Velden, Yme U.; van den Boorn, Jasper G.; Keller, Anna M.; Buurman, Wim A.; Theoret, Marc R.; Blom, Bianca; Restifo, Nicholas P.; Kruisbeek, Ada M.; Kastelein, Robert A.; Haanen, John B. A. G.

    2006-01-01

    The promising, but modest, clinical results of many human cancer vaccines indicate a need for vaccine adjuvants that can increase both the quantity and the quality of vaccine-induced, tumor-specific T cells. In this study we tested the immunological and antitumor effects of the proinflammatory

  16. Inflammatory responses and side effects generated by several adjuvant-containing vaccines in turbot.

    Science.gov (United States)

    Noia, M; Domínguez, B; Leiro, J; Blanco-Méndez, J; Luzardo-Álvarez, A; Lamas, J

    2014-05-01

    Several of the adjuvants used in fish vaccines cause adhesions in internal organs when they are injected intraperitoneally. We describe the damage caused by vaccines containing different adjuvants in the turbot Scophthalmus maximus and show that internal adhesions can be greatly reduced by injecting the fish in a specific way. Injection of fish with the needle directed towards the anterior part of the peritoneal cavity induced formation of a single cell-vaccine mass (CVM) that became attached to the parietal peritoneum. However, injection of the fish with the needle pointing in the opposite direction generated many small CVM that became attached to the visceral and parietal peritoneum and in some cases caused internal adhesions. We describe the structural and cellular changes in the adjuvant-induced CVMs. The CVMs mainly comprised neutrophils and macrophages, although most of the former underwent apoptosis, which was particularly evident from day 3 post-injection. The apoptotic cells were phagocytosed by macrophages, which were the dominant cell type from the first days onwards. All of the vaccines induced angiogenesis in the area of contact between the CVM and the mesothelium. Vaccines containing oil-based adjuvants or microspheres induced the formation of granulomas in the CVM; however, no granulomas were observed in the CVM induced by vaccines containing aluminium hydroxide or Matrix-Q(®) as adjuvants. All of the vaccines induced strong migration of cells to the peritoneal cavity. Although some of these cells remained unattached in the peritoneal cavity, most of them formed part of the CVM. We also observed migration of the cells from the peritoneal cavity to lymphoid organs, indicating bidirectional traffic of cells between the inflamed areas and these organs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Adjuvant-Mediated Epitope Specificity and Enhanced Neutralizing Activity of Antibodies Targeting Dengue Virus Envelope Protein

    Directory of Open Access Journals (Sweden)

    Denicar Lina Nascimento Fabris Maeda

    2017-09-01

    Full Text Available The heat-labile toxins (LT produced by enterotoxigenic Escherichia coli display adjuvant effects to coadministered antigens, leading to enhanced production of serum antibodies. Despite extensive knowledge of the adjuvant properties of LT derivatives, including in vitro-generated non-toxic mutant forms, little is known about the capacity of these adjuvants to modulate the epitope specificity of antibodies directed against antigens. This study characterizes the role of LT and its non-toxic B subunit (LTB in the modulation of antibody responses to a coadministered antigen, the dengue virus (DENV envelope glycoprotein domain III (EDIII, which binds to surface receptors and mediates virus entry into host cells. In contrast to non-adjuvanted or alum-adjuvanted formulations, antibodies induced in mice immunized with LT or LTB showed enhanced virus-neutralization effects that were not ascribed to a subclass shift or antigen affinity. Nonetheless, immunosignature analyses revealed that purified LT-adjuvanted EDIII-specific antibodies display distinct epitope-binding patterns with regard to antibodies raised in mice immunized with EDIII or the alum-adjuvanted vaccine. Notably, the analyses led to the identification of a specific EDIII epitope located in the EF to FG loop, which is involved in the entry of DENV into eukaryotic cells. The present results demonstrate that LT and LTB modulate the epitope specificity of antibodies generated after immunization with coadministered antigens that, in the case of EDIII, was associated with the induction of neutralizing antibody responses. These results open perspectives for the more rational development of vaccines with enhanced protective effects against DENV infections.

  18. Adjuvant solution for pandemic influenza vaccine production.

    Science.gov (United States)

    Clegg, Christopher H; Roque, Richard; Van Hoeven, Neal; Perrone, Lucy; Baldwin, Susan L; Rininger, Joseph A; Bowen, Richard A; Reed, Steven G

    2012-10-23

    Extensive preparation is underway to mitigate the next pandemic influenza outbreak. New vaccine technologies intended to supplant egg-based production methods are being developed, with recombinant hemagglutinin (rHA) as the most advanced program for preventing seasonal and avian H5N1 Influenza. Increased efforts are being focused on adjuvants that can broaden vaccine immunogenicity against emerging viruses and maximize vaccine supply on a worldwide scale. Here, we test protection against avian flu by using H5N1-derived rHA and GLA-SE, a two-part adjuvant system containing glucopyranosyl lipid adjuvant (GLA), a formulated synthetic Toll-like receptor 4 agonist, and a stable emulsion (SE) of oil in water, which is similar to the best-in-class adjuvants being developed for pandemic flu. Notably, a single submicrogram dose of rH5 adjuvanted with GLA-SE protects mice and ferrets against a high titer challenge with H5N1 virus. GLA-SE, relative to emulsion alone, accelerated induction of the primary immune response and broadened its durability against heterosubtypic H5N1 virus challenge. Mechanistically, GLA-SE augments protection via induction of a Th1-mediated antibody response. Innate signaling pathways that amplify priming of Th1 CD4 T cells will likely improve vaccine performance against future outbreaks of lethal pandemic flu.

  19. Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines

    Science.gov (United States)

    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. Gold glyconanoparticles coupled to listeriolysin O 91-99 peptide serve as adjuvant therapy against melanoma.

    Science.gov (United States)

    Calderon-Gonzalez, R; Terán-Navarro, H; García, I; Marradi, M; Salcines-Cuevas, D; Yañez-Diaz, S; Solis-Angulo, A; Frande-Cabanes, E; Fariñas, M C; Garcia-Castaño, A; Gomez-Roman, J; Penades, S; Rivera, F; Freire, J; Álvarez-Domínguez, C

    2017-08-03

    Dendritic cell-based (DC-based) vaccines are promising immunotherapies for cancer. However, several factors, such as the lack of efficient targeted delivery and the sources and types of DCs, have limited the efficacy of DCs and their clinical potential. We propose an alternative nanotechnology-based vaccine platform with antibacterial prophylactic abilities that uses gold glyconanoparticles coupled to listeriolysin O 91-99 peptide (GNP-LLO 91-99 ), which acts as a novel adjuvant for cancer therapy. GNP-LLO 91-99 , when used to vaccinate mice, exhibited dual antitumour activities, namely, the inhibition of tumour migration and growth and adjuvant activity for recruiting and activating DCs, including those from melanoma patients. GNP-LLO 91-99 nanoparticles caused tumour apoptosis and induced antigen- and melanoma-specific cytotoxic Th1 responses (P ≤ 0.5). We propose this adjuvant nanotherapy for preventing the progression of the first stages of melanoma.

  1. Radiation recall secondary to adjuvant docetaxel after balloon-catheter based accelerated partial breast irradiation

    International Nuclear Information System (INIS)

    Wong, Nathan W.; Wong, William W.; Karlin, Nina J.; Gray, Richard J.

    2010-01-01

    For early stage breast cancer, wide local excision and post-operative whole breast irradiation is a standard treatment. If adjuvant chemotherapy is recommended, radiation is usually given after completion of chemotherapy. In recent years, accelerated partial breast irradiation (APBI) with balloon-cathetered based brachytherapy has become an option for selected patients. For these patients, adjuvant chemotherapy would have to be administered after radiation. The sequence of treatment with radiation followed by chemotherapy results in increased risk of radiation recall reaction (RRD) in these patients. Docetaxel is becoming a more commonly used drug as adjuvant treatment for breast cancer. Here we report a case of docetaxel induced RRD after APBI with balloon-cathetered based brachytherapy. Such reaction would have an adverse impact on the cosmetic outcome and quality of life of the patient. For patients who develop an intense skin reaction after the administration of docetaxel following APBI, RRD should be considered in the differential diagnosis.

  2. Natural and synthetic saponin adjuvant QS-21 for vaccines against cancer

    Science.gov (United States)

    Ragupathi, Govind; Gardner, Jeffrey R; Livingston, Philip O; Gin, David Y

    2013-01-01

    One of the most widely used and potent immunological adjuvants is a mixture of soluble triterpene glycosides purified from the soap bark tree (Quillaja saponaria). Despite challenges in production, quality control, stability and toxicity, the QS-21 fraction from this extract has exhibited exceptional adjuvant properties for a range of antigens. It possesses an ability to augment clinically significant antibody and T-cell responses to vaccine antigens against a variety of infectious diseases, degenerative disorders and cancers. The recent synthesis of active molecules of QS-21 has provided a robust method to produce this leading vaccine adjuvant in high purity as well as to produce novel synthetic QS-21 congeners designed to induce increased immune responsiveness and decreased toxicity. PMID:21506644

  3. Successful adjuvant-free vaccination of BALB/c mice with mutated amyloid β peptides

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    Wahi Monika M

    2008-02-01

    Full Text Available Abstract Background A recent human clinical trial of an Alzheimer's disease (AD vaccine using amyloid beta (Aβ 1–42 plus QS-21 adjuvant produced some positive results, but was halted due to meningoencephalitis in some participants. The development of a vaccine with mutant Aβ peptides that avoids the use of an adjuvant may result in an effective and safer human vaccine. Results All peptides tested showed high antibody responses, were long-lasting, and demonstrated good memory response. Epitope mapping indicated that peptide mutation did not lead to epitope switching. Mutant peptides induced different inflammation responses as evidenced by cytokine profiles. Ig isotyping indicated that adjuvant-free vaccination with peptides drove an adequate Th2 response. All anti-sera from vaccinated mice cross-reacted with human Aβ in APP/PS1 transgenic mouse brain tissue. Conclusion Our study demonstrated that an adjuvant-free vaccine with different Aβ peptides can be an effective and safe vaccination approach against AD. This study represents the first report of adjuvant-free vaccines utilizing Aβ peptides carrying diverse mutations in the T-cell epitope. These largely positive results provide encouragement for the future of the development of human vaccinations for AD.

  4. Mitogenic Activity of a Water-Soluble Adjuvant (Bu-WSA) Obtained from Bacterionema matruchotii: IV. Synergistic Effects of Bu-WSA on Concanavalin A-Induced Proliferative Response of Human Peripheral Blood Lymphocytes.

    Science.gov (United States)

    Nitta, Toshimasa; Okumura, Seiichi; Tsushi, Masao; Nakano, Masayasu

    1982-07-01

    Butanol-extracted water-soluble adjuvant (Bu-WSA) obtained from Bacterionema matruchotii was cultured with peripheral blood mononuclear cells (PBM) in the presence of sub- and/or supra-optimal mitogenic concentrations of concanavalin A (Con A). The addition of Bu-WSA resulted in increased tritiated thymidine incorporation above that produced by Con A alone. Bu-WSA by itself is not mitogenic for PBM and in fact produced a decrease in thymidine uptake compared to the control. We investigated the response of subpopulation(s) of PBM to Bu-WSA, Con A and a mixture of Bu-WSA and Con A. Separation of PBM into purified T cells, B cells and macrophages showed that cell-cell cooperation of T cells with B cells or macrophages is necessary for the observed synergistic effect of Bu-WSA with Con A. A marked increase in thymidine incorporation by the mixture of T and B cell populations occurred, while only a small amount of thymidine was incorporated when the B cell population was absent. Mitomycin treatment revealed that the response could be ascribed to the T-cell response with a B-cell helper effect. Moreover, Con A and Bu-WSA appeared to act on the same T cell population. This model may provide unique information about the activation of human peripheral blood T cells compared with the activation of these cells by other mitogens. © owned by Center for Academic Publications Japan (Publisher).

  5. Mitogenic activity of a water-soluble adjuvant (Bu-WSA) obtained from Bacterionema matruchotii. IV. Synergistic effects of Bu-WSA on Concanavalin A-induced proliferative response of human peripheral blood lymphocytes.

    Science.gov (United States)

    Nitta, T; Okumura, S; Tsushi, M; Nakano, M

    1982-01-01

    Butanol-extracted water-soluble adjuvant (Bu-WSA) obtained from Bacterionema matruchotii was cultured with peripheral blood mononuclear cells (PBM) in the presence of sub- and/or supra-optimal mitogenic concentrations of concanavalin A (Con A). The addition of Bu-WSA resulted in increased tritiated thymidine incorporation above that produced by Con A alone. Bu-WSA by itself is not mitogenic for PBM and in fact produced a decrease in thymidine uptake compared to the control. We investigated the response of subpopulation(s) of PBM to Bu-WSA, Con A and a mixture of Bu-WSA and Con A. Separation of PBM into purified T cells, B cells and macrophages showed that cell-cell cooperation of T cells with B cells or macrophages is necessary for the observed synergistic effect of Bu-WSA with Con A. A marked increase in thymidine incorporation by the mixture of T and B cell populations occurred, while only a small amount of thymidine was incorporated when the B cell population was absent. Mitomycin treatment revealed that the response could be ascribed to the T-cell response with a B-cell helper effect. Moreover, Con A and Bu-WSA appeared to act on the same T cell population. This model may provide unique information about the activation of human peripheral blood T cells compared with the activation of these cells by other mitogens.

  6. Adjuvanted vaccines: Aspects of immunosafety and modes of action

    NARCIS (Netherlands)

    Aalst, Susan van

    2017-01-01

    New developments in vaccine design shift towards safe, though sometimes less immunogenic, subunit and synthetic antigens. Therefore, the majority of current vaccines require adjuvants to increase immunogenicity. Most adjuvants available were developed empirically and their mode of action is only

  7. Saponin-based adjuvants create a highly effective anti-tumor vaccine when combined with in situ tumor destruction.

    NARCIS (Netherlands)

    Brok, M.H.M.G.M. den; Nierkens, S.; Wagenaars, J.A.L.; Ruers, T.J.M.; Schrier, C.C.; Rijke, E.O.; Adema, G.J.

    2012-01-01

    Today's most commonly used microbial vaccines are essentially composed of antigenic elements and a non-microbial adjuvant, and induce solid amounts of antibodies. Cancer vaccines mostly aim to induce anti-tumor CTL-responses, which require cross-presentation of tumor-derived antigens by dendritic

  8. THE USE OF ADJUVANTS IN STUDIES ON INFLUENZA IMMUNIZATION

    Science.gov (United States)

    Salk, Jonas E.; Laurent, Angela M.

    1952-01-01

    Untoward reactions at the site of inoculation were not observed in monkeys vaccinated with influenza virus incorporated in a water-in-oil emulsion without acid-fast bacilli. Studies were then made to measure some of the dimensions of antigenicity of these emulsions to evaluate the extent of the immunologic adjuvant effect. This included measurements of height and persistence of the antibody response to inoculation and measurements of the extent to which the vaccine could be diluted and still induce antibody formation; i.e., antigenic extinction. In addition, comparisons were made of the rates of development of hemagglutination-inhibiting, virus-neutralizing, and complement-fixing antibody activities to determine the relationship among these three properties of the serum of immunized animals. It was found that levels of antibody many fold higher were induced by the virus-adjuvant mixtures as compared with virus in an aqueous menstruum, and that the level of antibody induced was related to the quantity of antigen incorporated in the emulsion. The stock vaccine when emulsified could be diluted 100,000-fold and was still active in antibody formation whereas a 100-fold dilution of the antigen without emulsification was essentially ineffective. Equivalent quantities of virus in 0.1 ml. or 1.0 ml. of emulsion induced antibody responses that were indistinguishable with respect to level or persistence. In comparing the course of antibody development it was found that hemagglutination-inhibiting, virus-neutralizing, and complement-fixing antibodies develop at different rates; careful analysis of the data derived from the present study together with other observations warrant the conclusion that these antibody activities are not present in constant proportion and are independent of one another. The implications of this observation and of the others mentioned above are discussed. PMID:14927797

  9. Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

    International Nuclear Information System (INIS)

    Sabolch, Aaron; Feng, Mary; Griffith, Kent; Hammer, Gary; Doherty, Gerard; Ben-Josef, Edgar

    2011-01-01

    Purpose: To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma. Methods and Materials: Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocortical carcinoma at the University of Michigan's Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival. Results: Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030). Conclusions: Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.

  10. Adjuvant Biological Therapies in Chronic Leg Ulcers

    Directory of Open Access Journals (Sweden)

    Natalia Burgos-Alonso

    2017-11-01

    Full Text Available Current biological treatments for non-healing wounds aim to address the common deviations in healing mechanisms, mainly inflammation, inadequate angiogenesis and reduced synthesis of extracellular matrix. In this context, regenerative medicine strategies, i.e., platelet rich plasmas and mesenchymal stromal cell products, may form part of adjuvant interventions in an integral patient management. We synthesized the clinical experience on ulcer management using these two categories of biological adjuvants. The results of ten controlled trials that are included in this systematic review favor the use of mesenchymal stromal cell based-adjuvants for impaired wound healing, but the number and quality of studies is moderate-low and are complicated by the diversity of biological products. Regarding platelet-derived products, 18 controlled studies investigated their efficacy in chronic wounds in the lower limb, but the heterogeneity of products and protocols hinders clinically meaningful quantitative synthesis. Most patients were diabetic, emphasizing an unmet medical need in this condition. Overall, there is not sufficient evidence to inform routine care, and further clinical research is necessary to realize the full potential of adjuvant regenerative medicine strategies in the management of chronic leg ulcers.

  11. Laser vaccine adjuvants. History, progress, and potential.

    Science.gov (United States)

    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.

  12. Assessment of the adjuvant activity of mesoporous silica nanoparticles in recombinant Mycoplasma hyopneumoniae antigen vaccines

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    Veridiana Gomes Virginio

    2017-01-01

    Full Text Available The adjuvant potential of two mesoporous silica nanoparticles (MSNs, SBa-15 and SBa-16, was assessed in combination with a recombinant HSP70 surface polypeptide domain from Mycoplasma hyopneumoniae, the etiological agent of porcine enzootic pneumonia (PEP. The recombinant antigen (HSP70212-600, previously shown as immunogenic in formulation with classic adjuvants, was used to immunize BALB/c mice in combination with SBa-15 or SBa-16 MSNs, and the effects obtained with these formulations were compared to those obtained with alum, the adjuvant traditionally used in anti-PEP bacterins. The HSP70212-600 + SBa-15 vaccine elicited a strong humoral immune response, with high serum total IgG levels, comparable to those obtained using HSP70212-600 + alum. The HSP70212-600 + SBa-16 vaccine elicited a moderate humoral immune response, with lower levels of total IgG. The cellular immune response was assessed by the detection of IFN-γ, IL-4 and IL-10 in splenocyte culture supernatants. The HSP70212-600 + SBa-15 vaccine increased IFN-γ, IL-4 and IL-10 levels, while no stimulation was detected with the HSP70212-600 + SBa-16 vaccine. The HSP70212-600 + SBa-15 vaccine induced a mixed Th1/Th2-type response, with an additional IL-10 mediated anti-inflammatory effect, both of relevance for an anti-PEP vaccine. Alum adjuvant controls stimulated an unspecific cellular immune response, with similar levels of cytokines detected in mice immunized either with HSP70212-600 + alum or with the adjuvant alone. The better humoral and cellular immune responses elicited in mice indicated that SBa-15 has adjuvant potential, and can be considered as an alternative to the use of alum in veterinary vaccines. The use of SBa-15 with HSP70212-600 is also promising as a potential anti-PEP subunit vaccine formulation.

  13. [Critical analysis of reference studies on aluminium-based adjuvants toxicokinetics].

    Science.gov (United States)

    Masson, J-D; Crépeaux, G; Authier, F-J; Exley, C; Gherardi, R K

    2017-07-01

    We reviewed the three reference toxicokinetic studies commonly used to suggest innocuity of aluminum (Al)-based adjuvants. A single experimental study was carried out using isotopic 26 Al (Flarend et al., 1997). This study ignored adjuvant cell capture. It was conducted over a short period of time (28 days) and used only two rabbits per adjuvant. At the endpoint, Al retention was 78% for aluminum phosphate and 94% for aluminum hydroxide, both results being incompatible with quick elimination of vaccine-derived Al in urines. Tissue distribution analysis omitted three important retention sites: the injected muscle, the draining lymph node and bone. Two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to the oral Minimal Risk Level (MRL) extrapolated from animal studies. Keith et al., 2002 used a too high MRL (2mg/kg/d), an erroneous model of 100% immediate absorption of vaccine Al, and did not consider renal and blood-brain barrier immaturity. Mitkus et al. (2011) only considered absorbed Al, with erroneous calculations of absorption duration. They ignored particulate Al captured by immune cells, which play a role in systemic diffusion and the neuro-inflammatory potential of the adjuvant. MRL they used was both inappropriate (oral Al vs injected adjuvant) and far too high (1mg/kg/d) with regard to experimental studies of Al-induced memory and behavioral changes. Both paucity and serious weaknesses of these studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including post-natal and adult exposures, to ensure innocuity and restore population confidence in Al-containing vaccines. Copyright © 2017 Académie Nationale de Pharmacie. All rights reserved.

  14. Rationally Designed TLR4 Ligands for Vaccine Adjuvant Discovery

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    Kelsey A. Gregg

    2017-05-01

    Full Text Available Adjuvant properties of bacterial cell wall components like MPLA (monophosphoryl lipid A are well described and have gained FDA approval for use in vaccines such as Cervarix. MPLA is the product of chemically modified lipooligosaccharide (LOS, altered to diminish toxic proinflammatory effects while retaining adequate immunogenicity. Despite the virtually unlimited number of potential sources among bacterial strains, the number of useable compounds within this promising class of adjuvants are few. We have developed bacterial enzymatic combinatorial chemistry (BECC as a method to generate rationally designed, functionally diverse lipid A. BECC removes endogenous or introduces exogenous lipid A-modifying enzymes to bacteria, effectively reprogramming the lipid A biosynthetic pathway. In this study, BECC is applied within an avirulent strain of Yersinia pestis to develop structurally distinct LOS molecules that elicit differential Toll-like receptor 4 (TLR4 activation. Using reporter cell lines that measure NF-κB activation, BECC-derived molecules were screened for the ability to induce a lower proinflammatory response than Escherichia coli LOS. Their structures exhibit varied, dose-dependent, TLR4-driven NF-κB activation with both human and mouse TLR4 complexes. Additional cytokine secretion screening identified molecules that induce levels of tumor necrosis factor alpha (TNF-α and interleukin-8 (IL-8 comparable to the levels induced by phosphorylated hexa-acyl disaccharide (PHAD. The lead candidates demonstrated potent immunostimulation in mouse splenocytes, human primary blood mononuclear cells (PBMCs, and human monocyte-derived dendritic cells (DCs. This newly described system allows directed programming of lipid A synthesis and has the potential to generate a diverse array of TLR4 agonist candidates.

  15. Pharmaceutical formulations as immunological adjuvants

    Energy Technology Data Exchange (ETDEWEB)

    O' Hagan, D T

    1987-01-01

    The aim of this work was to enhance the immune responses to ovalbumin (OVA) following its oral administration, by the association of the protein with colloidal carriers, which may protect the protein from degradation in the gastrointestinal tract and/or facilitate its uptake across the intestine. An enzyme linked immunosorbent assay (ELISA) was established for the determination of rat anti-OVA antibodies and an immunization protocol was established to induce a statistically significant salivary antibody response to OVA in the rat. A radioimmunoassay for the determination of rat anti-OVA antibodies was also established, to confirm the ELISA results. Methods were established to determine the extent of incorporation or adsorption of OVA into or onto the colloidal carrier formations.

  16. Freund's vaccine adjuvant promotes Her2/Neu breast cancer

    International Nuclear Information System (INIS)

    Cotroneo, Michelle S; Haag, Jill D; Stapel, Nicholas R; Waller, Jordy L; Woditschka, Stephan; Gould, Michael N

    2009-01-01

    Inflammation has been linked to the etiology of many organ-specific cancers. Indirect evidence suggests a possible role for inflammation in breast cancer. We investigated whether the systemic inflammation induced by Freund's adjuvant (FA) promotes mammary carcinogenesis in a rat model in which cancer is induced by the neu oncogene. The effects of FA on hyperplastic mammary lesions and mammary carcinomas were determined in a neu-induced rat model. The inflammatory response to FA treatment was gauged by measuring acute phase serum haptoglobin. In addition, changes in cell proliferation and apoptosis following FA treatment were assessed. Rats receiving FA developed twice the number of mammary carcinomas as controls. Systemic inflammation following FA treatment is chronic, as shown by a doubling of the levels of the serum biomarker, haptoglobin, 15 days following initial treatment. We also show that this systemic inflammation is associated with the increased growth of hyperplastic mammary lesions. This increased growth results from a higher rate of cellular proliferation in the absence of changes in apoptosis. Our data suggests that systemic inflammation induced by Freund's adjuvant (FA) promotes mammary carcinogenesis. It will be important to determine whether adjuvants currently used in human vaccines also promote breast cancer

  17. Intranasal H5N1 vaccines, adjuvanted with chitosan derivatives, protect ferrets against highly pathogenic influenza intranasal and intratracheal challenge.

    Directory of Open Access Journals (Sweden)

    Alex J Mann

    Full Text Available We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI intratracheal and intranasal challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments or intranasally (CSN adjuvanted and placebo treatments only with clade 1 HPAI A/Vietnam/1194/2004 (H5N1 virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals. This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant

  18. DNA Vaccine Electroporation and Molecular Adjuvants

    Science.gov (United States)

    2016-03-16

    Suschak and Schmaljohn DNA Vaccine Electroporation and Molecular Adjuvants 1 Abstract To date, there is no protective vaccine for Ebola virus...the formulation of DNA launched virus-like particles (VLP). In this case, the antigen is encoded in one DNA plasmid, while structural proteins are...Virol, 2010. 155(12): p. 2083-103. 2. Feldmann, H. and T.W. Geisbert, Ebola haemorrhagic fever. Lancet, 2011. 377(9768): p. 849-62. 3. Hart, M.K

  19. Parenteral adjuvant potential of recombinant B subunit of Escherichia coli heat-labile enterotoxin

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    Carlos Eduardo Pouey da Cunha

    Full Text Available BACKGROUND The B subunit of Escherichia coli heat-labile enterotoxin (LTB is a potent mucosal immune adjuvant. However, there is little information about LTB's potential as a parenteral adjuvant. OBJECTIVES We aimed at evaluating and better understanding rLTB's potential as a parenteral adjuvant using the fused R1 repeat of Mycoplasma hyopneumoniae P97 adhesin as an antigen to characterise the humoral immune response induced by this construct and comparing it to that generated when aluminium hydroxide is used as adjuvant instead. METHODS BALB/c mice were immunised intraperitoneally with either rLTBR1 or recombinant R1 adsorbed onto aluminium hydroxide. The levels of systemic anti-rR1 antibodies (total Ig, IgG1, IgG2a, and IgA were assessed by enzyme-linked immunosorbent assay (ELISA. The ratio of IgG1 and IgG2a was used to characterise a Th1, Th2, or mixed Th1/Th2 immune response. FINDINGS Western blot confirmed rR1, either alone or fused to LTB, remained antigenic; anti-cholera toxin ELISA confirmed that LTB retained its activity when expressed in a heterologous system. Mice immunised with the rLTBR1 fusion protein produced approximately twice as much anti-rR1 immunoglobulins as mice vaccinated with rR1 adsorbed onto aluminium hydroxide. Animals vaccinated with either rLTBR1 or rR1 adsorbed onto aluminium hydroxide presented a mixed Th1/Th2 immune response. We speculate this might be a result of rR1 immune modulation rather than adjuvant modulation. Mice immunised with rLTBR1 produced approximately 1.5-fold more serum IgA than animals immunised with rR1 and aluminium hydroxide. MAIN CONCLUSIONS The results suggest that rLTB is a more powerful parenteral adjuvant than aluminium hydroxide when administered intraperitoneally as it induced higher antibody titres. Therefore, we recommend that rLTB be considered an alternative adjuvant, even if different administration routes are employed.

  20. Adjuvant activity of peanut, cottonseed and rice oils on cellular and humoral response

    Directory of Open Access Journals (Sweden)

    Erika Freitas

    2013-04-01

    Full Text Available The potentiality of the usage of vegetable oils such as soybean, corn, olive, sesame, murici seed, rapeseed, linseed, rice and cashew nuts as adjuvant of the humoral and cellular immune response has been recently shown. In the present work, besides of evaluating the adjuvant action of peanut, cottonseed and rice oils on humoral and cellular immune responses against ovalbumin (OVA we also evaluated the protective immune response induced by Leishmania antigens. The peanut oil significantly increased the synthesis of anti-ovalbumin antibodies in the primary response, but it did not favor cellular response. Concerning mice immunized with L. amazonensis antigens emulsified with peanut oil exacerbated skin lesions and lymph node parasite load what suggests stimulation of the Th2 immune response and down regulation of Th1 response. The cottonseed oil was shown to have adjuvant effect to the humoral response, stimulating a secondary response and also favored the delayed-type hypersensitivity (DTH response to OVA. The rice oil stimulated a strong DTH reaction to OVA and enhanced the synthesis of antibodies after the third dose. Mice immunized with L. amazonensis antigens emulsified with rice oil or cotton seed oil were protected from developing skin lesions and lymph node parasite load. These results emphasize the interest and importance of the vegetable oils as tools in different procedures of immunization and their differential role in relation to the other adjuvant under usage.

  1. Effectiveness of Brucella abortus lipopolysaccharide as an adjuvant for tuberculin PPD.

    Science.gov (United States)

    Jamalan, Mostafa; Ardestani, Susan Kaboudanian; Zeinali, Majid; Mosaveri, Nader; Mohammad Taheri, Mohammad

    2011-01-01

    Bacterial lipopolysaccharide (LPS) has T-helper 1 (Th1) immunostimulatory activities but because of toxicity and pyrogenicity cannot be used as an adjuvant. Brucella abortus LPS has less toxicity and no pyrogenic properties in comparison to other bacterial LPS. In the current study, the immunostimulatory properties of B. abortus LPS were evaluated for its adjuvant activity. Tuberculin purified protein derivative (PPD) from Mycobacterium tuberculosis was extracted and after anion-exchange chromatography on Q-sepharose column, two fractions (17 and 23), which dominantly contained 30- and 70-kDa antigens, were collected for immunological studies. BALB/c mice were immunized with four different antigen preparations (BCG, PPD, 17th and 23rd PPD fractions) along with complete Freund's adjuvant or B. abortus LPS. The T-cell immune response of mice was assessed by measurement of Th1-type cytokine (IFN-γ) and Th2-type cytokines (IL-5 and IL-10) levels. Also, the humoral immunity was evaluated by measuring the specific IgG levels. Our results showed that immunization of mice with 17th PPD fraction along with B. abortus LPS can induce a Th1-type cytokine response characterized with a high IFN-γ/IL-5 ratio, while immunization with PPD or 23rd PPD fraction along with the same adjuvant resulted to a mixed Th1/Th2-type cytokine response. Copyright © 2010 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.

  2. Melatonin and Fertoprotective Adjuvants: Prevention against Premature Ovarian Failure during Chemotherapy.

    Science.gov (United States)

    Jang, Hoon; Hong, Kwonho; Choi, Youngsok

    2017-06-07

    Premature ovarian failure is one of the side effects of chemotherapy in pre-menopausal cancer patients. Preservation of fertility has become increasingly important in improving the quality of life of completely recovered cancer patients. Among the possible strategies for preserving fertility such as ovarian tissue cryopreservation, co-treatment with a pharmacological adjuvant is highly effective and poses less of a burden on the human body. Melatonin is generally produced in various tissues and acts as a universally acting antioxidant in cells. Melatonin is now more widely used in various biological processes including treating insomnia and an adjuvant during chemotherapy. In this review, we summarize the information indicating that melatonin may be useful for reducing and preventing premature ovarian failure in chemotherapy-treated female patients. We also mention that many adjuvants other than melatonin are developed and used to inhibit chemotherapy-induced infertility. This information will give us novel insights on the clinical use of melatonin and other agents as fertoprotective adjuvants for female cancer patients.

  3. Endogenous and Exogenous Natural Adjuvants for Vaccine Development.

    Science.gov (United States)

    Bolhassani, Azam; Talebi, Somayeh; Anvar, Ali

    2017-01-01

    Objective & Background: Various adjuvants are usually co-injected with an antigen for stimulation of effective immune responses. Adjuvants are able to elicit innate immune responses at the injection site. Depending on the activated type of innate responses, adjuvants can modify the quality and quantity of adaptive immune responses. Their mechanisms of action in vaccine development include: a) enhancement of the total antibody titers; b) reduction of the antigen dose; c) induction of potent cell-mediated immunity; d) increase in the speed and duration of the protective response; e) stimulation of mucosal immunity; and f) cross-protection. Up to now, different exogenous adjuvants have been identified to boost immune responses including inorganic compounds, mineral oil, bacterial products, non-bacterial organics, detergents or Quil A, plant saponins, Freund's complete or incomplete adjuvants, and delivery systems. However, some immune responses can be generated in the absence of the exogenous adjuvants. Indeed, endogenous adjuvants released from the cells were known as the danger signals and immunogenic compounds. Several main endogenous adjuvants contain cytokines, chemokines, alarmins, dendritic cells (DCs), toll like receptor (TLR) ligands or agonists, and antibodies. In this review, the immune activities of the natural adjuvants especially endogenous adjuvants and their mechanisms of action are discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Impact of adjuvant chemotherapy for gliomatosis cerebri

    International Nuclear Information System (INIS)

    Kong, Doo-Sik; Nam, Do-Hyun; Kim, Sung Tae; Lee, Jung-Il; Suh, Yeon-Lim; Lim, Do Hoon; Kim, Won Seog; Kwon, Ki-Hoon; Park, Kwan; Kim, Jong Hyun

    2010-01-01

    Gliomatosis cerebri (GC) is characterized by a diffuse infiltration of tumor cells throughout CNS, however, few details are available about the chemotherapeutic effect on GC. The aim of this study was to investigate its clinical course and to determine the efficacy of chemotherapy for GC. Between Jan. 1999 and Dec. 2004, 37 GC patients were diagnosed by biopsy and treated with radiotherapy in a single institution. To determine the efficacy of chemotherapy for GC, we retrospectively reviewed their clinical courses. The study cohort was divided into 2 groups, those with and without receiving post-radiotherapy adjuvant chemotherapy such as temozolomide or nitrosourea-based chemotherapy. Nineteen patients with adjuvant chemotherapy were assigned to the chemotreatment group and 18 with radiotherapy alone were assigned to the control group. Mean survival for chemotreatment group and control group were 24.2 and 13.1 months, respectively (p = 0.045). Time to progression for these groups were 16.0 and 6.0 months, respectively (p = 0.007). Overall review of the clinical course of patients with GC provided that early appearance of new contrast-enhancing lesions within 6 months from the initial diagnosis and higher histological grade were closely associated with poor survival (p < 0.001 and p = 0.008). Adjuvant chemotherapy following radiotherapy could prolong the survival in patients with GC. In addition, newly developed contrast-enhanced lesions on the follow-up MR images indicate the progression of GC

  5. Adjuvant radiotherapy for stage I endometrial cancer.

    Science.gov (United States)

    Kong, A; Johnson, N; Cornes, P; Simera, I; Collingwood, M; Williams, C; Kitchener, H

    2007-04-18

    The role of adjuvant radiotherapy (both pelvic external beam radiotherapy and vaginal intracavity brachytherapy) in stage I endometrial cancer following total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH and BSO) remains unclear. To assess the efficacy of adjuvant radiotherapy following surgery for stage I endometrial cancer. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CancerLit, Physician Data Query (PDQ) of National Cancer Institute. Handsearching was also carried out where appropriate. Randomised controlled trials (RCTs) which compared adjuvant radiotherapy versus no radiotherapy following surgery for patients with stage I endometrial cancer were included. Quality of the studies was assessed and data collected using a predefined data collection form. The primary endpoint was overall survival. Secondary endpoints were locoregional recurrence, distant recurrence and endometrial cancer death. Data on quality of life (QOL) and morbidity were also collected. A meta-analysis on included trials was performed using the Cochrane Collaboration Review Manager Software 4.2. The meta-analysis was performed on four trials (1770 patients). The addition of pelvic external beam radiotherapy to surgery reduced locoregional recurrence, a relative risk (RR) of 0.28 (95% confidence interval (CI) 0.17 to 0.44, p ASTEC; Lukka) are awaited. External beam radiotherapy carries a risk of toxicity and should be avoided in stage 1 endometrial cancer patients with no high risk factors.

  6. Postoperative adjuvant therapy of colorectal carcinoma

    International Nuclear Information System (INIS)

    Scheithauer, W.

    1989-01-01

    Evaluating the results of controlled clinical trials, an attempt has been made to summarize the current status of adjuvant therapy in colorectal cancer. Several different adjuvant treatment approaches including immunotherapy, postoperative fibrinolysis, anticoagulation, pre- and postoperative radiotherapy when used as a single modality, have not resulted in any long-term survival benefit. Rather in contrast to previous experiences, recent prospective randomized trials have provided evidence for the efficacy of chemotherapy in the adjuvant treatment of colon and rectal cancer. Whereas its definitive role in the former disease remains somewhat controversial, for rectal cancer, it seems clear that combined modality therapy including polychemotherapy with or without radiation prolongs the disease-free interval, lowers the local recurrence rate, and may improve survival compared to surgery alone. Questions which remain to be answered by future clinical trials are related to the optimal duration and sequence of combined modality, to the role of different radiation sensitizers, and in both colon and rectal cancer, to the choice of the most effective systemtic chemotherapeutic drugs. (orig./MG) [de

  7. Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants.

    Science.gov (United States)

    Marty-Roix, Robyn; Vladimer, Gregory I; Pouliot, Kimberly; Weng, Dan; Buglione-Corbett, Rachel; West, Kim; MacMicking, John D; Chee, Jonathan D; Wang, Shixia; Lu, Shan; Lien, Egil

    2016-01-15

    Many immunostimulants act as vaccine adjuvants via activation of the innate immune system, although in many cases it is unclear which specific molecules contribute to the stimulatory activity. QS-21 is a defined, highly purified, and soluble saponin adjuvant currently used in licensed and exploratory vaccines, including vaccines against malaria, cancer, and HIV-1. However, little is known about the mechanisms of cellular activation induced by QS-21. We observed QS-21 to elicit caspase-1-dependent IL-1β and IL-18 release in antigen-presenting cells such as macrophages and dendritic cells when co-stimulated with the TLR4-agonist adjuvant monophosphoryl lipid A. Furthermore, our data suggest that the ASC-NLRP3 inflammasome is responsible for QS-21-induced IL-1β/IL-18 release. At higher concentrations, QS-21 induced macrophage and dendritic cell death in a caspase-1-, ASC-, and NLRP3-independent manner, whereas the presence of cholesterol rescued cell viability. A nanoparticulate adjuvant that contains QS-21 as part of a heterogeneous mixture of saponins also induced IL-1β in an NLRP3-dependent manner. Interestingly, despite the role NLRP3 plays for cellular activation in vitro, NLRP3-deficient mice immunized with HIV-1 gp120 and QS-21 showed significantly higher levels of Th1 and Th2 antigen-specific T cell responses and increased IgG1 and IgG2c compared with wild type controls. Thus, we have identified QS-21 as a nonparticulate single molecular saponin that activates the NLRP3 inflammasome, but this signaling pathway may contribute to decreased antigen-specific responses in vivo. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants*

    Science.gov (United States)

    Marty-Roix, Robyn; Vladimer, Gregory I.; Pouliot, Kimberly; Weng, Dan; Buglione-Corbett, Rachel; West, Kim; MacMicking, John D.; Chee, Jonathan D.; Wang, Shixia; Lu, Shan; Lien, Egil

    2016-01-01

    Many immunostimulants act as vaccine adjuvants via activation of the innate immune system, although in many cases it is unclear which specific molecules contribute to the stimulatory activity. QS-21 is a defined, highly purified, and soluble saponin adjuvant currently used in licensed and exploratory vaccines, including vaccines against malaria, cancer, and HIV-1. However, little is known about the mechanisms of cellular activation induced by QS-21. We observed QS-21 to elicit caspase-1-dependent IL-1β and IL-18 release in antigen-presenting cells such as macrophages and dendritic cells when co-stimulated with the TLR4-agonist adjuvant monophosphoryl lipid A. Furthermore, our data suggest that the ASC-NLRP3 inflammasome is responsible for QS-21-induced IL-1β/IL-18 release. At higher concentrations, QS-21 induced macrophage and dendritic cell death in a caspase-1-, ASC-, and NLRP3-independent manner, whereas the presence of cholesterol rescued cell viability. A nanoparticulate adjuvant that contains QS-21 as part of a heterogeneous mixture of saponins also induced IL-1β in an NLRP3-dependent manner. Interestingly, despite the role NLRP3 plays for cellular activation in vitro, NLRP3-deficient mice immunized with HIV-1 gp120 and QS-21 showed significantly higher levels of Th1 and Th2 antigen-specific T cell responses and increased IgG1 and IgG2c compared with wild type controls. Thus, we have identified QS-21 as a nonparticulate single molecular saponin that activates the NLRP3 inflammasome, but this signaling pathway may contribute to decreased antigen-specific responses in vivo. PMID:26555265

  9. A Protective Vaccine against Chlamydia Genital Infection Using Vault Nanoparticles without an Added Adjuvant

    OpenAIRE

    Janina Jiang; Guangchao Liu; Valerie A. Kickhoefer; Leonard H. Rome; Lin-Xi Li; Stephen J. McSorley; Kathleen A. Kelly

    2017-01-01

    Chlamydia trachomatis genital infection is the most common sexually transmitted bacterial disease, causing a significant burden to females due to reproductive dysfunction. Intensive screening and antibiotic treatment are unable to completely prevent female reproductive dysfunction, thus, efforts have become focused on developing a vaccine. A major impediment is identifying a safe and effective adjuvant which induces cluster of differentiation 4 (CD4) cells with attributes capable of halting g...

  10. Adjuvant chemotherapy for rectal cancer: Is it needed?

    Science.gov (United States)

    Milinis, Kristijonas; Thornton, Michael; Montazeri, Amir; Rooney, Paul S

    2015-01-01

    Adjuvant chemotherapy has become a standard treatment of advanced rectal cancer in the West. The benefits of adjuvant chemotherapy after surgery alone have been well established. However, controversy surrounds the use adjuvant chemotherapy in patients who received preoperative chemoradiotherapy, despite it being recommended by a number of international guidelines. Results of recent multicentre randomised control trials showed no benefit of adjuvant chemotherapy in terms of survival and rates of distant metastases. However, concerns exist regarding the quality of the studies including inadequate staging modalities, out-dated chemotherapeutic regimens and surgical approaches and small sample sizes. It has become evident that not all the patients respond to adjuvant chemotherapy and more personalised approach should be employed when considering the benefits of adjuvant chemotherapy. The present review discusses the strengths and weaknesses of the current evidence-base and suggests improvements for future studies. PMID:26677436

  11. Overview of Vaccine Adjuvants: Introduction, History, and Current Status.

    Science.gov (United States)

    Shah, Ruchi R; Hassett, Kimberly J; Brito, Luis A

    2017-01-01

    Adjuvants are included in sub-unit or recombinant vaccines to enhance the potency of poorly immunogenic antigens. Adjuvant discovery is as complex as it is a multidiscplinary intersection of formulation science, immunology, toxicology, and biology. Adjuvants such as alum, which have been in use for the past 90 years, have illustrated that adjuvant research is a methodical process. As science advances, new analytical tools are developed which allows us to delve deeper into the various mechanisms that generates a potent immune response. Additionally, these new techniques help the field learn about our existing vaccines and what makes them safe, and effective, allowing us to leverage that in the next generation of vaccines. Our goal in this chapter is to define the concept, need, and mechanism of adjuvants in the vaccine field while describing its history, present use, and future prospects. More details on individual adjuvants and their formulation, development, mechanism, and use will be covered in depth in the next chapters.

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

    International Nuclear Information System (INIS)

    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

  13. Experimental inflammation following dural application of complete Freund's adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage

    DEFF Research Database (Denmark)

    Lundblad, Cornelia; Haanes, Kristian A; Grände, Gustaf

    2015-01-01

    , following dural application of complete Freund's adjuvant (CFA) or inflammatory soup (IS) on brain and trigeminal microvascular passage. METHODS: In order to address this issue, we induced local inflammation in male Sprague-Dawley-rats dura mater by the addition of CFA or IS directly on the dural surface...

  14. Complications following surgery and adjuvant irradiation in rectal carcinoma. Komplikationen nach Operation und nach adjuvanter Bestrahlung beim Rektumkarzinom

    Energy Technology Data Exchange (ETDEWEB)

    Suhr, P.; Limmer, J. (Ulm Univ. (Germany, F.R.). Universitaetsklinikum)

    1991-04-12

    Colorectal cancer is one of the most common human malignancies. Adjuvant irradiation can decrease the risk of recurrence and subsequently the associated morbidity compared with surgery alone. The rate of radiation-induced complications amounts to approximately 10%, which is substantially lower than the frequency of observed local failure. (orig.).

  15. CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization.

    Science.gov (United States)

    Sundling, Christopher; Schön, Karin; Mörner, Andreas; Forsell, Mattias N E; Wyatt, Richard T; Thorstensson, Rigmor; Karlsson Hedestam, Gunilla B; Lycke, Nils Y

    2008-12-01

    Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in non-human primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env.

  16. Liposome-Based Adjuvants for Subunit Vaccines: Formulation Strategies for Subunit Antigens and Immunostimulators

    Directory of Open Access Journals (Sweden)

    Signe Tandrup Schmidt

    2016-03-01

    Full Text Available The development of subunit vaccines has become very attractive in recent years due to their superior safety profiles as compared to traditional vaccines based on live attenuated or whole inactivated pathogens, and there is an unmet medical need for improved vaccines and vaccines against pathogens for which no effective vaccines exist. The subunit vaccine technology exploits pathogen subunits as antigens, e.g., recombinant proteins or synthetic peptides, allowing for highly specific immune responses against the pathogens. However, such antigens are usually not sufficiently immunogenic to induce protective immunity, and they are often combined with adjuvants to ensure robust immune responses. Adjuvants are capable of enhancing and/or modulating immune responses by exposing antigens to antigen-presenting cells (APCs concomitantly with conferring immune activation signals. Few adjuvant systems have been licensed for use in human vaccines, and they mainly stimulate humoral immunity. Thus, there is an unmet demand for the development of safe and efficient adjuvant systems that can also stimulate cell-mediated immunity (CMI. Adjuvants constitute a heterogeneous group of compounds, which can broadly be classified into delivery systems or immunostimulators. Liposomes are versatile delivery systems for antigens, and they can carefully be customized towards desired immune profiles by combining them with immunostimulators and optimizing their composition, physicochemical properties and antigen-loading mode. Immunostimulators represent highly diverse classes of molecules, e.g., lipids, nucleic acids, proteins and peptides, and they are ligands for pattern-recognition receptors (PRRs, which are differentially expressed on APC subsets. Different formulation strategies might thus be required for incorporation of immunostimulators and antigens, respectively, into liposomes, and the choice of immunostimulator should ideally be based on knowledge regarding the

  17. The mechanism of action of MF59 - an innately attractive adjuvant formulation.

    Science.gov (United States)

    O'Hagan, D T; Ott, G S; De Gregorio, E; Seubert, A

    2012-06-19

    MF59 is a safe and effective vaccine adjuvant which was originally approved to be included in a licensed influenza vaccine to be used in the elderly in Europe in 1997. The MF59 adjuvanted influenza vaccine (Fluad™) is now licensed in more than 20 countries worldwide and more than 85 million doses have been administered. More recently the vaccine adjuvant has also been shown to be safe and effective in young children and resulted in a significant increase in influenza vaccine efficacy in a controlled clinical trial in Europe. Since the early days of its discovery we have explored the mechanism of action of MF59, using a variety of available techniques. In recent years we have explored more thoroughly the mechanism of action using new and more sophisticated techniques. It is remarkable how consistent the data has been, using a variety of different approaches both in several small animal models and also using human immune cells in vitro. Here we present a summary of all the work performed to date on the mechanism of action of MF59 and we present a unified theory based on the accumulated data of how it exerts its adjuvant effects. A key element of the mechanism of action appears to be the creation of a transient 'immunocompetent' local environment at the injection site, resulting in the recruitment of key immune cells, which are able to take up antigen and adjuvant and transport them to the local lymph nodes, where the immune response is induced. This recruitment appears to be triggered by the induction of a chemokine driven gradient by the impact of MF59 on local cells, which are activated to secrete further chemokines, which are recruitment factors for more immune cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Towards an understanding of the adjuvant action of aluminium

    Science.gov (United States)

    Marrack, Philippa; McKee, Amy S.; Munks, Michael W.

    2011-01-01

    The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work. PMID:19247370

  19. Effect of DETOX as an adjuvant for melanoma vaccine.

    Science.gov (United States)

    Schultz, N; Oratz, R; Chen, D; Zeleniuch-Jacquotte, A; Abeles, G; Bystryn, J C

    1995-04-01

    The identification of effective adjuvants is critical for tumor vaccine development. Towards this end, we examined whether the immunogenicity of a melanoma vaccine could be potentiated by DETOX, an adjuvant consisting of monophosphoryl lipid A (MPL) and purified mycobacterial cell-wall skeleton (CWS). Nineteen patients with resected stage III melanoma were immunized with a polyvalent melanoma antigen vaccine (40 micrograms) admixed with DETOX, q3 wks x 4. Seven patients received vaccine + low-dose DETOX (10 micrograms MPL + 100 micrograms CWS) and 12 received vaccine + high-dose DETOX (20 micrograms MPL + 200 micrograms CWS). A non-randomized control group of 35 patients was treated similarly with 40 micrograms vaccine + alum. One week after the fourth vaccine immunization, melanoma antibodies were increased over baseline in 7/7 (100%) patients treated with vaccine + low-dose DETOX, 8/12 (67%) patients treated with vaccine + high-dose DETOX, and in 4/19 (21%) of vaccine + alum patients. For the entire DETOX group, the antibody response rate was 15/19 (79%) compared 4/19 (21%) in the alum group (p or = 15 mm increase in DTH response over baseline) was induced in 50% of the entire DETOX group versus in 47% of the alum group. Median disease-free (DF) survival for the entire DETOX group was 17.8 months compared with 32.1 months in the alum group (p DETOX markedly potentiated antibody but had little effect on DTH responses to melanoma vaccine immunization. It did not appear to improve disease-free survival in comparison to alum in this non-randomized study.

  20. Analysis of the dose-sparing effect of adjuvanted Sabin-inactivated poliovirus vaccine (sIPV).

    Science.gov (United States)

    Li, Zhuofan; Ding, Wenting; Guo, Qi; Liu, Ze; Zhu, Zhe; Song, Shaohui; Li, Weidong; Liao, Guoyang

    2018-03-30

    Sabin-based inactivated poliovirus vaccine(sIPV) is gradually replacing live-attenuated oral polio vaccine(OPV). Sabin-inactivated poliovirus vaccine(sIPV) has played a vital role in reducing economic burden of poliomyelitis and maintaining appropriate antibody levels in the population. However, due to its high cost and limited manufacturing capacity, sIPV cannot reach its full potential for global poliovirus eradication in developing countries. Therefore, to address this situation, we designed this study to evaluate the dose-sparing effects of AS03, CpG oligodeoxynucleotides (CpG-ODN) and polyinosinic:polycytidylic acid (PolyI:C) admixed with sIPV in rats. Our results showed that a combination of 1/4-dose sIPV adjuvanted with AS03 or AS03 with BW006 provides a seroconversion rate similar to that of full-dose sIPV without adjuvant and that, this rate is 5-fold higher than that of 1/4-dose sIPV without adjuvant after the first immunization. The combination of AS03 or AS03 with BW006 as an adjuvant effectively reduced sIPV dose by at least 4-fold and induced both humoral and cellular immune responses. Therefore, our study revealed that the combination of AS03 or AS03 with BW006 is a promising adjuvant for sIPV development.

  1. Enhancement of Mucosal Immunogenicity of Viral Vectored Vaccines by the NKT Cell Agonist Alpha-Galactosylceramide as Adjuvant

    Directory of Open Access Journals (Sweden)

    Shailbala Singh

    2014-10-01

    Full Text Available Gene-based vaccination strategies, specifically viral vectors encoding vaccine immunogens are effective at priming strong immune responses. Mucosal routes offer practical advantages for vaccination by ease of needle-free administration, and immunogen delivery at readily accessible oral/nasal sites to efficiently induce immunity at distant gut and genital tissues. However, since mucosal tissues are inherently tolerant for induction of immune responses, incorporation of adjuvants for optimal mucosal vaccination strategies is important. We report here the effectiveness of alpha-galactosylceramide (α-GalCer, a synthetic glycolipid agonist of natural killer T (NKT cells, as an adjuvant for enhancing immunogenicity of vaccine antigens delivered using viral vectors by mucosal routes in murine and nonhuman primate models. Significant improvement in adaptive immune responses in systemic and mucosal tissues was observed by including α-GalCer adjuvant for intranasal immunization of mice with vesicular stomatitis virus vector encoding the model antigen ovalbumin and adenoviral vectors expressing HIV env and Gag antigens. Activation of NKT cells in systemic and mucosal tissues along with significant increases in adaptive immune responses were observed in rhesus macaques immunized by intranasal and sublingual routes with protein or adenovirus vectored antigens when combined with α-GalCer adjuvant. These results support the utility of α-GalCer adjuvant for enhancing immunogenicity of mucosal vaccines delivered using viral vectors.

  2. Influence of the number and interval of treatment cycles on cytokine-induced killer cells and their adjuvant therapeutic effects in advanced non-small-cell lung cancer (NSCLC).

    Science.gov (United States)

    Gu, Yuanlong; Lv, Huimin; Zhao, Juan; Li, Qi; Mu, Guannan; Li, Jiade; Wuyang, Jiazi; Lou, Ge; Wang, Ruitao; Zhang, Yanqiao; Huang, Xiaoyi

    2017-09-01

    Cytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). A total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry. After in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group (P=0.0189 and P=0.0129, respectively). The median OS of the ACT≥4cycles subgroup was significantly longer than that of the ACTcells in patients who received ≥4cycles of ACT was higher than that in patients treated with cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells. Systematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC. Copyright © 2017. Published by Elsevier B.V.

  3. N-(2-hydroxy) propyl-3-trimethylammonium chitosan chloride: An immune-enhancing adjuvant for hepatitis E virus recombinant polypeptide vaccine in mice.

    Science.gov (United States)

    Tao, Wei; Zheng, Hai-Qun; Fu, Ting; He, Zhuo-Jing; Hong, Yan

    2017-08-03

    Adjuvants are essential for enhancing vaccine potency by improving the humoral and/or cell-mediated immune response to vaccine antigens. This study was performed to evaluate the immuno-enhancing characteristic of N-(2-hydroxy) propyl-3-trimethylammonium chitosan chloride (HTCC), the cationically modified chitosan, as an adjuvant for hepatitis E virus (HEV) recombinant polypeptide vaccine. Animal experiments showed that HTCC provides adjuvant activity when co-administered with HEV recombinant polypeptide vaccine by intramuscularly route. Vaccination using HTCC as an adjuvant was associated with increases of the serum HEV-specific IgG antibodies, splenocytes proliferation and the growths of CD4 + CD8 - T lymphocytes and IFN-γ-secreting T lymphocytes in peripheral blood. These findings suggested that HTCC had strong immuno-enhancing effect. Our findings are the first to demonstrate that HTCC is safe and effective in inducing a good antibody response and stimulating Th1-biased immune responses for HEV recombinant polypeptide vaccine.

  4. Assessment of efficacy and safety of various adjuvant formulations with a total soluble extract of Trichinella spiralis

    Directory of Open Access Journals (Sweden)

    Aucouturier J.

    2001-06-01

    Full Text Available Trichinellosis, a re-emerging zoonosis in several countries and pig, is the main species responsible for its transmission to human. Vaccination of swine could be an alternative to prevent the risk of human contamination. In order to develop an efficient and safe inactivate vaccine, the choice of the adjuvant is an important issue. The aim of this study was to develop and select potent and safe adjuvants by screening them in an experimental model with a crude soluble antigen from L1 muscular larvae (ML of Trichinella spiralis (Ts. The efficacy was checked by the quantification of specific antibody levels. Specific and non-specific IgE antibody levels were also assessed. Safety was checked by the assessment of the local reaction at the injection site.Various Montanide® ISA adjuvant formulations including water in oil, oil in water and multiphasic emulsions, but also nanoparticles or microbeads were tested. The results clearly showed differences between the antibody responses induced by the adjuvants and demonstrated the necessity to use an adjuvant to obtain a specific IgG (IgG1or lgG2a response directed against the total soluble extract of Ts. All the formulations enhanced the humoral immune response. The origin of the oil contained in the emulsions played an important role on the efficacy. Indeed emulsions based on mineral oils were more efficient than those based on metabolisable oils. However it was linked with stronger local reactions. Multiphasic and oil in water emulsions but also nanoparticles failed to induce 1gG2a antibody levels. Microbeads and water in oil formulations based on mineral oils were more efficient. This experimentation allowed then the selection of several adjuvants which efficacy will be further Investigated by a challenge test and an analysis of the cellular populations involved in the mechanism of the immune response.

  5. Tolerance induction after specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A in children.

    Science.gov (United States)

    Rosewich, M; Schulze, J; Eickmeier, O; Telles, T; Rose, M A; Schubert, R; Zielen, S

    2010-06-01

    Specific immunotherapy (SIT) is a well-established and clinically effective treatment for allergic diseases. A pollen allergoid formulated with the T helper type 1 (Th1)-inducing adjuvant monophosphoryl lipid A (MPL) facilitates short-term SIT. Little is known about mechanisms of tolerance induction in this setting. In a prospective study, 34 patients allergic to grass pollen (25 male, nine female, median age 10.2 years) received a total of 44 SIT courses (20 in the first, 24 in the second) with MPL-adjuvanted pollen allergoids. Immunogenicity was measured by levels of specific immunoglobulin G (IgG(grass)) and IgG4(grass) by antibody blocking properties on basophil activation, and by induction of CD4(+), CD25(+) and forkhead box P3 (FoxP3(+)) regulatory T cells (T(reg)). Specific IgG and IgG4 levels increased only slightly in the first year of SIT. In the second year these changes reached significance (P allergoids formulated with the Th1-inducing adjuvant MPL needs at least two courses to establish tolerance.

  6. Inhibitory effects of Cynodon dactylon L. on inflammation and oxidative stress in adjuvant treated rats.

    Science.gov (United States)

    Sindhu, G; Ratheesh, M; Shyni, G L; Helen, A

    2009-01-01

    Cynodon dactylon is one of the 10 auspicious herbs that constitute the group Dasapushpam in Ayurveda. Traditionally Cynodon dactylon L. is used against many chronic inflammatory diseases in India. The present study was carried out to evaluate the protective effect of Cynodon dactylon against rats with adjuvant- induced arthritis. Arthritis was induced by intradermal injection of complete Freund's adjuvant into the right hind paw produce inflammation of the joint. A significant increase in the levels of inflammatory mediators, myeloperoxidase, nitrite, C-reactive protein, ceruloplasmin was observed. This was associated with oxidative stress with a marked reduction in the activity of catalase, superoxide dismutase, glutathione peroxidase and the levels of glutathione, vitamins C and E and an increase in the lipid peroxidation as indicated by the higher levels of thiobarbituric acid reactive substances. Cynodon dactylon (20mg/kg/b.wt) was orally administered to arthritic rats after adjuvant injection produced a significant attenuation in the inflammatory response, oxidative stress and ameliorated the arthritic changes to near normal conditions. Hence, the results of this study clearly indicate that Cynodon dactylon extract has a promising protective role against arthritis.

  7. Vaccine Adjuvants in Fish Vaccines Make a Difference: Comparing Three Adjuvants (Montanide ISA763A Oil, CpG/Poly I:C Combo and VHSV Glycoprotein Alone or in Combination Formulated with an Inactivated Whole Salmonid Alphavirus Antigen

    Directory of Open Access Journals (Sweden)

    Hanna L. Thim

    2014-03-01

    Full Text Available Most commercial vaccines offered to the aquaculture industry include inactivated antigens (Ag formulated in oil adjuvants. Safety concerns are related to the use of oil adjuvants in multivalent vaccines for fish, since adverse side effects (e.g., adhesions can appear. Therefore, there is a request for vaccine formulations for which protection will be maintained or improved, while the risk of side effects is reduced. Here, by using an inactivated salmonid alphavirus (SAV as the test Ag, the combined use of two Toll-like receptor (TLR ligand adjuvants, CpG oligonucleotides (ODNs and poly I:C, as well as a genetic adjuvant consisting of a DNA plasmid vector expressing the viral haemorrhagic septicaemia virus (VHSV glycoprotein (G was explored. VHSV-G DNA vaccine was intramuscularly injected in combination with intraperitoneal injection of either SAV Ag alone or combined with the oil adjuvant, Montanide ISA763, or the CpG/polyI:C combo. Adjuvant formulations were evaluated for their ability to boost immune responses and induce protection against SAV in Atlantic salmon, following cohabitation challenge. It was observed that CpG/polyI:C-based formulations generated the highest neutralizing antibody titres (nAbs before challenge, which endured post challenge. nAb responses for VHSV G-DNA- and oil-adjuvanted formulations were marginal compared to the CpG/poly I:C treatment. Interestingly, heat-inactivated sera showed reduced nAb titres compared to their non-heated counterparts, which suggests a role of complement-mediated neutralization against SAV. Consistently elevated levels of innate antiviral immune genes in the CpG/polyI:C injected groups suggested a role of IFN-mediated responses. Co-delivery of the VHSV-G DNA construct with either CpG/polyI:C or oil-adjuvanted SAV vaccine generated higher CD4 responses in head kidney at 48 h compared to injection of this vector or SAV Ag alone. The results demonstrate that a combination of pattern recognizing

  8. Protein antigen adsorption to the DDA/TDB liposomal adjuvant

    DEFF Research Database (Denmark)

    Hamborg, Mette; Jorgensen, Lene; Bojsen, Anders Riber

    2013-01-01

    Understanding the nature of adjuvant-antigen interactions is important for the future design of efficient and safe subunit vaccines, but remains an analytical challenge. We studied the interactions between three model protein antigens and the clinically tested cationic liposomal adjuvant composed...... of dimethyldioctadecylammonium (DDA) and trehalose 6,6'-dibehenate (TDB)....

  9. Adjuvant chemotherapy for endometrial cancer after hysterectomy

    Science.gov (United States)

    Johnson, Nick; Bryant, Andrew; Miles, Tracie; Hogberg, Thomas; Cornes, Paul

    2014-01-01

    Background Endometrial adenocarcinoma (womb cancer) is a malignant growth of the lining (endometrium) of the womb (uterus). It is distinct from sarcomas (tumours of the uterine muscle). Survival depends the risk of microscopic metastases after surgery. Adjuvant (postoperative) chemotherapy improves survival from some other adenocarcinomas, and there is evidence that endometrial cancer is sensitive to cytotoxic therapy. This systematic review examines the effect of chemotherapy on survival after hysterectomy for endometrial cancer. Objectives To assess efficacy of adjuvant (postoperative) chemotherapy for endometrial cancer. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE up to August 2010, registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Selection criteria Randomised controlled trials (RCTs) comparing adjuvant chemotherapy with any other adjuvant treatment or no other treatment. Data collection and analysis We used a random-effects meta-analysis to assess hazard ratios (HR) for overall and progression-free survival and risk ratios (RR) to compare death rates and site of initial relapse. Main results Five RCTs compared no additional treatment with additional chemotherapy after hysterectomy and radiotherapy. Four trials compared platinum based combination chemotherapy directly with radiotherapy. Indiscriminate pooling of survival data from 2197 women shows a significant overall survival advantage from adjuvant chemotherapy (RR (95% CI) = 0.88 (0.79 to 0.99)). Sensitivity analysis focused on trials of modern platinum based chemotherapy regimens and found the relative risk of death to be 0.85 ((0.76 to 0.96); number needed to treat for an additional beneficial outcome (NNT) = 25; absolute risk reduction = 4% (1% to 8%)). The HR for overall survival is 0.74 (0.64 to 0.89), significantly

  10. Liposomes containing monophosphoryl lipid A and QS-21 serve as an effective adjuvant for soluble circumsporozoite protein malaria vaccine FMP013.

    Science.gov (United States)

    Genito, Christopher J; Beck, Zoltan; Phares, Timothy W; Kalle, Fanta; Limbach, Keith J; Stefaniak, Maureen E; Patterson, Noelle B; Bergmann-Leitner, Elke S; Waters, Norman C; Matyas, Gary R; Alving, Carl R; Dutta, Sheetij

    2017-07-05

    Malaria caused by Plasmodium falciparum continues to threaten millions of people living in the tropical parts of the world. A vaccine that confers sterile and life-long protection remains elusive despite more than 30years of effort and resources invested in solving this problem. Antibodies to a malaria vaccine candidate circumsporozoite protein (CSP) can block invasion and can protect humans against malaria. We have manufactured the Falciparum Malaria Protein-013 (FMP013) vaccine based on the nearly full-length P. falciparum CSP 3D7 strain sequence. We report here immunogenicity and challenge data on FMP013 antigen in C57BL/6 mice formulated with two novel adjuvants of the Army Liposome Formulation (ALF) series and a commercially available adjuvant Montanide ISA 720 (Montanide) as a control. ALF is a liposomal adjuvant containing a synthetic monophosphoryl lipid A (3D-PHAD®). In our study, FMP013 was adjuvanted with ALF alone, ALF containing aluminum hydroxide (ALFA) or ALF containing QS-21 (ALFQ). Adjuvants ALF and ALFA induced similar antibody titers and protection against transgenic parasite challenge that were comparable to Montanide. ALFQ was superior to the other three adjuvants as it induced higher antibody titers with improved boosting after the third immunization, higher serum IgG2c titers, and enhanced protection. FMP013+ALFQ also augmented the numbers of splenic germinal center-derived activated B-cells and antibody secreting cells compared to Montanide. Further, FMP013+ALFQ induced antigen-specific IFN-γ ELISPOT activity, CD4 + T-cells and a T H 1-biased cytokine profile. These results demonstrate that soluble CSP can induce a potent and sterile protective immune response when formulated with the QS-21 containing adjuvant ALFQ. Comparative mouse immunogenicity data presented here were used as the progression criteria for an ongoing non-human primate study and a regulatory toxicology study in preparation for a controlled human malaria infection (CHMI

  11. Immune adjuvant activity of the olive, soybean and corn oils

    Directory of Open Access Journals (Sweden)

    Ana Claudia Marinho da Silva

    2016-08-01

    Full Text Available In the last half of the century, a large amount of substances has been used as immune adjuvant. The immune adjuvant effect of olive, soybean and corn oils in Swiss mice immunized with ovalbumin (OVA plus aluminum hydroxide or emulsified in Marcol, soybean, olive or corn oils was evaluated through the OVA-specific antibodies determined by ELISA and Passive Cutaneous Anaphylaxis. In this work the comparison of the intensity of the immune response was established by the Bayesian analysis. The adjuvant effect of the vegetable oils was shown to be more effective than aluminium hydroxide. Regarding to OVA-specific IgE synthesis, olive oil had the slowest adjuvant effect of the three vegetable oils. Accordingly, olive oil was the most convenient among the vegetable oils to be used as immune adjuvant, since it stimulated a higher production of OVA-specific Ig and lower levels of anti-OVA IgE.

  12. Vaxjo: A Web-Based Vaccine Adjuvant Database and Its Application for Analysis of Vaccine Adjuvants and Their Uses in Vaccine Development

    Directory of Open Access Journals (Sweden)

    Samantha Sayers

    2012-01-01

    Full Text Available Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO in the Web Ontology Language (OWL format.

  13. Vaxjo: a web-based vaccine adjuvant database and its application for analysis of vaccine adjuvants and their uses in vaccine development.

    Science.gov (United States)

    Sayers, Samantha; Ulysse, Guerlain; Xiang, Zuoshuang; He, Yongqun

    2012-01-01

    Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO) in the Web Ontology Language (OWL) format.

  14. Gamma-irradiated influenza A virus provides adjuvant activity to a co-administered poorly immunogenic SFV vaccine in mice.

    Directory of Open Access Journals (Sweden)

    Rachelle eBabb

    2014-06-01

    Full Text Available Many currently available inactivated vaccines require 'adjuvants' to maximise the protective immune responses generated against the antigens of interest. Recent studies in mice with gamma-irradiated influenza A virus (γ-FLU have shown its superior efficacy compared to other forms of inactivated FLU vaccines and its ability to induce both potent type-I interferon (IFN-I responses and the IFN-I associated partial lymphocyte activation. Commonly, IFN-I responses induced by adjuvants, combined in vaccine preparations, have been shown to effectively enhance the immunogenicity of the antigens of interest. Therefore, we investigated the potential adjuvant activity of γ-FLU and the possible effect on antibody responses against co-administrated antigens, using gamma-irradiated Semliki Forest Virus (γ-SFV as the experimental vaccine in mice. Our data show that co-vaccination with γ-FLU and γ-SFV resulted in enhanced SFV-specific antibody responses in terms of increased titres by 6 fold and greater neutralisation efficacy, when compared to vaccination with γ-SFV alone. This study provides promising evidence related to the possible use of γ-FLU as an adjuvant to poorly immunogenic vaccines without compromising the vaccine efficacy of γ-FLU.

  15. Induction of the 'ASIA' syndrome in NZB/NZWF1 mice after injection of complete Freund's adjuvant (CFA).

    Science.gov (United States)

    Bassi, N; Luisetto, R; Del Prete, D; Ghirardello, A; Ceol, M; Rizzo, S; Iaccarino, L; Gatto, M; Valente, M L; Punzi, L; Doria, A

    2012-02-01

    Adjuvants, commonly used in vaccines, may be responsible for inducing autoimmunity and autoimmune diseases, both in humans and mice. The so-called 'ASIA' (Autoimmune/inflammatory Syndrome Induced by Adjuvants) syndrome has been recently described, which is caused by the exposure to a component reproducing the effect of adjuvants. The aim of our study was to evaluate the effect of injection of complete Freund's adjuvant (CFA) in NZB/NZWF1 mice, a lupus-prone murine model. We injected 10 NZB/NZWF1 mice with CFA/PBS and 10 with PBS, three times, 3 weeks apart, and followed-up until natural death. CFA-injected mice developed both anti-double-stranded DNA and proteinuria earlier and at higher levels than the control group. Proteinuria-free survival rate and survival rate were significantly lower in CFA-treated mice than in the control mice (p = 0.002 and p = 0.001, respectively). Histological analyses showed a more severe glomerulonephritis in CFA-injected mice compared with the control mice. In addition, lymphoid hyperplasia in spleen and lungs, myocarditis, and vasculitis were observed in the former, but not in the latter group. In conclusion, the injection of CFA in NZB/NZWF1 mice accelerated autoimmune manifestations resembling 'ASIA' syndrome in humans.

  16. Polysaccharides from Ganoderma formosanum function as a Th1 adjuvant and stimulate cytotoxic T cell response in vivo.

    Science.gov (United States)

    Pi, Chia-Chen; Chu, Ching-Liang; Lu, Chu-Ying; Zhuang, Yu-Jing; Wang, Cheng-Li; Yu, Yao-Hsuan; Wang, Hui-Yi; Lin, Chih-Chung; Chen, Chun-Jen

    2014-01-09

    The fungus of Ganoderma is a basidiomycete that possesses a variety of pharmacological effects and has been used in traditional Asian medicine for centuries. Ganoderma formosanum is a native Ganoderma species isolated in Taiwan, and we have previously demonstrated that PS-F2, a polysaccharide fraction purified from the submerged culture broth of G. formosanum, exhibits immunostimulatory properties in macrophages. In this study, we further characterized the adjuvant functions of PS-F2. In vitro, PS-F2 stimulated dendritic cells (DCs) to produce proinflammatory cytokines, including TNF-α, interleukin (IL)-6, and IL-12/IL-23 p40. PS-F2 also stimulated DCs to express the maturation markers CD40, CD80, CD86, and MHC class II. In a murine splenocyte culture, PS-F2 treatment resulted in elevated expression of T-bet and interferon (IFN)-γ in T lymphocytes. When used as an adjuvant in vivo with the ovalbumin (OVA) antigen, PS-F2 stimulated OVA-specific antibody production and primed IFN-γ production in OVA-specific T lymphocytes. PS-F2-adjuvated immunization also induced OVA-specific CTLs, which protected mice from a challenge with tumor cells expressing OVA. Collectively, our data show that PS-F2 functions as an adjuvant capable of inducing a Th1-polarized adaptive immune response, which would be useful in vaccines against viruses and tumors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Curdlan sulfate-O-linked quaternized chitosan nanoparticles: potential adjuvants to improve the immunogenicity of exogenous antigens via intranasal vaccination.

    Science.gov (United States)

    Zhang, Shu; Huang, Shengshi; Lu, Lu; Song, Xinlei; Li, Pingli; Wang, Fengshan

    2018-01-01

    The development of ideal vaccine adjuvants for intranasal vaccination can provide convenience for many vaccinations. As an ideal intranasal vaccine adjuvant, it should have the properties of assisting soluble antigens to pass the mucosal barrier and potentiating both systemic and mucosal immunity via nasal administration. By using the advantages of polysaccharides, which can promote both T-helper 1 and 2 responses, curdlan sulfate (CS)- O -(2-hydroxyl)propyl-3-trimethyl ammonium chitosan chloride ( O -HTCC) nanoparticles were prepared by interacting CS with O -HTCC, and the adjuvancy of the nanoparticles was investigated. The results showed that the polysaccharide-based nanoparticles induced the proliferation and activation of antigen-presenting cells. High protein-loading efficiency was obtained by testing with the model antigen ovalbumin (Ova), and the Ova adsorbed onto the cationic CS/ O -HTCC complexes was taken up easily by the epithelium. To evaluate the capacity of the Ova/CS/ O -HTCC nanoparticles for immune enhancement in vivo, we collected and analyzed immunocytes, serum, and mucosal lavage fluid from intranasally vaccinated mice. The results showed that Ova/CS/ O -HTCC nanoparticles induced activation and maturation of antigen-presenting cells and provoked the proliferation and differentiation of lymphocytes more significantly compared to the immunization of Ova mixed with aluminum hydroxide gel. Furthermore, CS/ O -HTCC evoked a significantly higher level of Ova-specific antibodies. Therefore, these results suggest that CS/ O -HTCC nanoparticles are ideal vaccine adjuvants for soluble antigens used in intranasal or mucosal vaccination.

  18. Quadrantectomy and adjuvant radiotherapy for breast cancer

    International Nuclear Information System (INIS)

    Gabriele, A.M.; Boidi Trotti, A.; Tardy, A.

    1987-01-01

    The conservative treatment of early breast cancer always requires irradiation of residual mammary tissue. The preliminary results obtained in 45 early breast cancer patients, who received quadrantectomy plus axillary dissection, followed by radiation of residual breast are reported. Radiation was performed by the two opposed field technique. In some cases the residual breast tissue was compressed using a special accessory provided with the Theratron 780. In addition to the tumor dose of 50 GY, 10 GY boots was added to the surgical scar using 7 MeV electrons. The 6 patients with positive axillary nodes received 6 courses of adjuvant chemotherapy (CMF) after radiotherapy. All patients are currently alive and free of disease. The 64% (29 patients) were followed up for at least 5 years, and 36% (16 patients) for at least 3 years. Only 2 cases of local recurrence were encountered (4,4%). The esthetic result was satisfactory in all cases. No side effects due to treatment were noted

  19. Multiple cardiac complications after adjuvant therapy for breast cancer: the importance of echocardiography. A case report and review of the literature.

    Science.gov (United States)

    Gurghean, Adriana Luminita; Savulescu-Fiedler, Ilinca; Mihailescu, Anca

    2017-01-31

    Cardiovascular complications induced by adjuvant cancer therapies may become symptomatic after many years, being responsible for increased morbidity and mortality in long-term survivors. We report a case of a 54-year old female admitted for severe heart failure induced by myocardial and valvular damage after postoperative adjuvant therapy for left breast cancer 6 years ago. Her recent history revealed nonST elevation myocardial infarction in the absence of significant cardiovascular risk factors. Transthoracic echocardiography, tissue Doppler imaging and speckle-tracking imaging revealed severe biventricular systolic dysfunction, severe mitral and tricuspid regurgitation and severe pulmonary hypertension.

  20. Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant.

    Science.gov (United States)

    Li, Xiangming; Fujio, Masakazu; Imamura, Masakazu; Wu, Douglass; Vasan, Sandhya; Wong, Chi-Huey; Ho, David D; Tsuji, Moriya

    2010-07-20

    The glycolipid alpha-galactosylceramide (alpha-GalCer) has been shown to bind CD1d molecules to activate invariant natural killer T (iNKT) cells, and subsequently induce activation of various immune-competent cells, including dendritic cells, thereby providing a significant adjuvant effect for various vaccines. However, in phase I clinical trials, alpha-GalCer was shown to display only marginal biological activity. In our search for a glycolipid that can exert more potent stimulatory activity against iNKT cells and dendritic cells and produce an adjuvant effect superior to alpha-GalCer, we performed step-wise screening assays on a focused library of 25 alpha-GalCer analogues. Assays included quantification of the magnitude of stimulatory activity against human iNKT cells in vitro, binding affinity to human and murine CD1d molecules, and binding affinity to the invariant t cell receptor of human iNKT cells. Through this rigorous and iterative screening process, we have identified a lead candidate glycolipid, 7DW8-5, that exhibits a superior adjuvant effect than alpha-GalCer on HIV and malaria vaccines in mice.

  1. Bacillus subtilis spores as vaccine adjuvants: further insights into the mechanisms of action.

    Directory of Open Access Journals (Sweden)

    Renata Damásio de Souza

    Full Text Available Bacillus subtilis spores have received growing attention regarding potential biotechnological applications, including the use as probiotics and in vaccine formulations. B. subtilis spores have also been shown to behave as particulate vaccine adjuvants, promoting the increase of antibody responses after co-administration with antigens either admixed or adsorbed on the spore surface. In this study, we further evaluated the immune modulatory properties of B. subtilis spores using a recombinant HIV gag p24 protein as a model antigen. The adjuvant effects of B. subtilis spores were not affected by the genetic background of the mouse lineage and did not induce significant inflammatory or deleterious effects after parenteral administration. Our results demonstrated that co-administration, but not adsorption to the spore surface, enhanced the immunogenicity of that target antigen after subcutaneous administration to BALB/c and C57BL/6 mice. Spores promoted activation of antigen presenting cells as demonstrated by the upregulation of MHC and CD40 molecules and enhanced secretion of pro-inflammatory cytokines by murine dendritic cells. In addition, in vivo studies indicated a direct role of the innate immunity on the immunomodulatory properties of B. subtilis spores, as demonstrated by the lack of adjuvant effects on MyD88 and TLR2 knockout mouse strains.

  2. Association of chitosan and aluminium as a new adjuvant strategy for improved vaccination.

    Science.gov (United States)

    Lebre, F; Bento, D; Ribeiro, J; Colaço, M; Borchard, G; de Lima, M C Pedroso; Borges, O

    2017-07-15

    The use of particulate adjuvants offers an interesting possibility to enhance and modulate the immune responses elicited by vaccines. Aluminium salts have been extensively used as vaccine adjuvants, but they lack the capacity to induce a strong cellular and mucosal immune response. Taking this into consideration, in this study we designed a new antigen delivery system combining aluminium salts with chitosan. Chitosan-aluminium nanoparticles (CH-Al NPs) exhibited a mean diameter of 280nm and a positive surface charge. The newly developed CH-Al NPs are more stable at physiological environment than classical CH NPs, showing no cytotoxic effects and revealing potential as a delivery system for a wide range of model antigens. In vivo studies showed that mice immunized with hepatitis B surface antigen (HBsAg)-containing CH NPs display high anti-HBsAg IgG titers in the serum, as well as the highest antigen-specific IgG on vaginal washes. Furthermore, in contrast to mice receiving antigen alone, mice immunized with the particulate adjuvant were able to elicit IgG2c antibody titers and exhibited higher antigen-specific IFN-γ levels in splenocytes. In conclusion, we established that CH-Al NPs, combining two immunostimulants to enhance both humoral and cellular immune responses, are a safe and promising system for antigen delivery. Our findings point towards their potential in future vaccination approaches. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Adjuvant radiation for vulvar carcinoma: improved local control

    International Nuclear Information System (INIS)

    Faul, Clare M.; Mirmow, Dwight; Huang Qingshon; Gerszten, Kristina; Day, Roger; Jones, Mirka W.

    1997-01-01

    Purpose: Local recurrence is a significant problem following primary surgery for advanced vulva carcinoma. The objectives of this study were to evaluate the impact of adjuvant vulvar radiation on local control in high risk patients and the impact of local recurrence on overall survival. Methods and Materials: From 1980-1994, 62 patients with invasive vulva carcinoma and either positive or close (less 8 mm) margins of excision were retrospectively studied. Thirty-one patients were treated with adjuvant radiation therapy to the vulva and 31 patients were observed after surgery. Kaplan-Meier estimates and the Cox proportional hazard regression model were used to evaluate the effect of adjuvant radiation therapy on local recurrence and overall survival. Independent prognostic factors for local recurrence and survival were also assessed. Results: Local recurrence occurred in 58% of observed patients and 16% in patients treated with adjuvant radiation therapy. Adjuvant radiation therapy significantly reduced local recurrence rates in both the close margin and positive margin groups (p = 0.036, p = 0.0048). On both univariate and multivariate analysis adjuvant radiation and margins of excision were significant prognostic predictors for local control. Significant determinants of actuarial survival included International Federation of Gynecologists and Obstetricians (FIGO) stage, percentage of pathologically positive inguinal nodes and margins of excision. The positive margin observed group had a significantly poorer actuarial 5 year survival than the other groups (p = 0.0016) and adjuvant radiation significantly improved survival for this group. The 2 year actuarial survival after developing local recurrence was 25%. Local recurrence was a significant predictor for death from vulva carcinoma (risk ratio 3.54). Conclusion: Local recurrence is a common occurrence in high risk patients. In this study adjuvant radiation therapy significantly reduced local recurrence rates and

  4. Adjuvant Treatment for Older Women with Invasive Breast Cancer

    Science.gov (United States)

    Jolly, Trevor A; Williams, Grant R; Bushan, Sita; Pergolotti, Mackenzi; Nyrop, Kirsten A; Jones, Ellen L; Muss, Hyman B

    2016-01-01

    Older women experience a large share of breast cancer incidence and death. With the projected rise in the number of older cancer patients, adjuvant chemo-, radiation and endocrine therapy management will become a key component of breast cancer treatment in older women. Many factors influence adjuvant treatment decisions including patient preferences, life expectancy and tumor biology. Geriatric assessment predicts important outcomes, identifies key deficits, and can aid in the decision making process. This review utilizes clinical vignettes to illustrate core principles in adjuvant management of breast cancer in older women and suggests an approach incorporating life expectancy and geriatric assessment. PMID:26767315

  5. Adjuvant radiotherapy and risk of contralateral breast cancer

    International Nuclear Information System (INIS)

    Storm, H.H.; Blettner, M.; Pedersen, J.

    1992-01-01

    To evaluate the relationship between high-dose radiotherapy and secondary breast cancer, a nested and matched case-control study in the cohort of breast cancer patients in Denmark was conducted. Radiation dose to the contralateral breast was reconstructed by medical physicists for each of the 529 cases and 529 controls, 82.4% of each group was treated with radiation. The average breast dose was 2.51 Gy, and a 20% increased risk was expected for this population at average age 51 years. There was no evidence that radiotherapy increased the overall risk of second breast cancer (RR=1.04), although the possibility of a RR as high as 1.46 could not be excluded. There was little indication that the risk varied over categories of radiation dose, time since exposure, or age at exposure. Thus, data provides additional evidence that there is little if any risk of radiation induced breast cancer associated with exposure of breast tissue to low-dose radiation (e.g., from mammographic X-rays or adjuvant radiotherapy) in later life. (author). 9 refs., 1 fig., 1 tab

  6. Chitosan-adjuvanted Mycoplasma gallisepticum bacterin via intraocular administration enhances Mycoplasma gallisepticum protection in commercial layers.

    Science.gov (United States)

    Limsatanun, A; Sasipreeyajan, J; Pakpinyo, S

    2018-06-01

    Mycoplasma gallisepticum (MG) causes respiratory signs and economic losses in the poultry industry. MG vaccination is one of the effective prevention and control measures that have been used around the world. Our previous study demonstrated that chitosan-adjuvanted MG bacterin could effectively reduce pathological lesions induced by MG and that chitosan could be used as an adjuvant in MG bacterin. The present study determining the efficacy of MG bacterins against the Thai MG strain was based on vaccine programs. Seven groups (25 layers/group) were received MG bacterins containing 0.5% chitosan or a commercial bacterin via intramuscular (IM) or intraocular (IO) route at 6 and 10 wk of age. Sham-negative and sham-positive controls were groups 1 and 2, respectively. Group 3: IM route of chitosan bacterin followed by IM route of chitosan bacterin; group 4: commercial bacterin via IM route followed by chitosan bacterin via IO route; group 5: commercial bacterin via IM route followed by commercial bacterin via IM route; group 6: chitosan bacterin via IM followed by chitosan bacterin via IO route; and group 7: chitosan bacterin via IO route followed by chitosan bacterin via IO route were determined. At 16 wk of age, all groups, excluding group 1, were challenged intratracheally with 0.1 mL containing Thai MG strain 107 colony-forming unit. At 17, 18, and 20 wk of age, 5 birds in each group were bled for serological testing and swabbed at the choanal cleft for the quantitative real-time PCR assay, the euthanized and necropsied. The results showed that birds vaccinated with a commercial intramuscular bacterin followed by an intraocularly chitosan adjuvant bacterin showed the best protection against the MG challenge. The study indicated that chitosan could be the effective mucosal adjuvant and increased the effectiveness of MG bacterin.

  7. Adjuvant chemotherapy in early breast cancer.

    Science.gov (United States)

    Ejlertsen, Bent

    2016-05-01

    these CMF regimens has not been compared within the context of a randomised trial. Shifting from the 77B's classic CMF regimen to the 82B four-weekly IV regimen or the 89B three-weekly IV regimen was associated with a 30% increased risk of a DFS event in a multivariate analysis of a population-based cohort study. Furthermore, the four-weekly regimen used in 82B was associated with a 40% increase in mortality. The strengths of the design include identical selection criteria, uniform and prospective registration of treatment, tumour and patient characteristics. Caution is still required due to the non-experimental design of the comparison. Another finding was a substantial difference in the risk of amenorrhoea; and while 15% of patients aged 40 or younger in 77B had regular menses throughout chemotherapy, the corresponding percentage was 37 in 82B and 47 in 89B. The DBCG in collaboration with a Swedish and a Dutch centre participating in the DBCG trial 89B compared CMF with ovarian ablation in premenopausal high-risk breast cancer patients with ER-positive tumours. No significant differences were found in DFS or OS in the preplanned analysis, suggesting that the benefits of CMF may, at least in part, be explained by ovarian suppression in premenopausal patients with ER-positive tumours. However, these results are not clinically useful by themselves as other chemotherapy regimens have been more efficacious, and knowledge is still lacking regarding the benefits from adding ovarian suppression to chemotherapy plus tamoxifen. The results from the DBCG 77B and 82C are in accordance with other large adjuvant trials and the EBCTCG meta-analyses. The benefits obtained with any individual anticancer drug are largely determined by the cancer (somatic) genome; and by being a molecular target of anthracyclines, TOP2A aberrations could obviously be associated with cancer drug benefits. In the DBCG 89D, a significant heterogeneity was observed between a beneficial effect on DFS and OS

  8. An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants.

    Science.gov (United States)

    Fox, Christopher B; Haensler, Jean

    2013-07-01

    With the exception of alum, emulsion-based vaccine adjuvants have been administered to far more people than any other adjuvant, especially since the 2009 H1N1 influenza pandemic. The number of clinical safety and immunogenicity evaluations of vaccines containing emulsion adjuvants has correspondingly mushroomed. In this review, the authors introduce emulsion adjuvant composition and history before detailing the most recent findings from clinical and postmarketing data regarding the effects of emulsion adjuvants on vaccine immunogenicity and safety, with emphasis on the most widely distributed emulsion adjuvants, MF59® and AS03. The authors also present a summary of other emulsion adjuvants in clinical development and indicate promising avenues for future emulsion-based adjuvant development. Overall, emulsion adjuvants have demonstrated potent adjuvant activity across a number of disease indications along with acceptable safety profiles.

  9. Adjuvant Therapy: Treatment to Keep Cancer from Returning

    Science.gov (United States)

    ... significant side effects, and these treatments don't benefit everyone. Types of cancer treatment that are used as adjuvant therapy include: Chemotherapy. Chemotherapy uses drugs to kill cancer cells throughout ...

  10. Activity of glycated chitosan and other adjuvants to PDT vaccines

    Science.gov (United States)

    Korbelik, Mladen; Banáth, Judit; Čiplys, Evaldas; Szulc, Zdzislaw; Bielawska, Alicja; Chen, Wei R.

    2015-03-01

    Glycated chitosan (GC), a water soluble galactose-conjugated natural polysaccharide, has proven to be an effective immunoadjuvant for treatment of tumors based on laser thermal therapy. It was also shown to act as adjuvant for tumor therapy with high-intensity ultrasound and in situ photodynamic therapy (PDT). In the present study, GC was examined as potential adjuvant to PDT-generated cancer vaccine. Two other agents, pure calreticulin protein and acid ceramidase inhibitor LCL521, were also tested as prospective adjuvants for use in conjunction with PDT vaccines. Single treatment with GC, included with PDT vaccine cells suspension, improved the therapeutic efficacy when compared to vaccine alone. This attractive prospect of GC application remains to be carefully optimized and mechanistically elucidated. Both calreticulin and LCL521 proved also effective adjuvants when combined with PDT vaccine tumor treatment.

  11. Immunomodulators as adjuvants for vaccines and antimicrobial therapy.

    Science.gov (United States)

    Nicholls, Erin F; Madera, Laurence; Hancock, Robert E W

    2010-12-01

    A highly effective strategy for combating infectious diseases is to enhance host defenses using immunomodulators, either preventatively, through vaccination, or therapeutically. The effectiveness of many vaccines currently in use is due in part to adjuvants, molecules that have little immunogenicity by themselves but which help enhance and appropriately skew the immune response to an antigen. The development of new vaccines necessitates the development of new types of adjuvants to ensure an appropriate immune response. Herein, we review commonly used vaccine adjuvants and discuss promising adjuvant candidates. We also discuss various other immunomodulators (namely cytokines, Toll-like receptor agonists, and host defense peptides) that are, or have potential to be, useful for antimicrobial therapies that exert their effects by boosting host immune responses rather than targeting pathogens directly.

  12. Engineering of an Inhalable DDA/TDB Liposomal Adjuvant

    DEFF Research Database (Denmark)

    Ingvarsson, Pall Thor; Yang, Mingshi; Mulvad, Helle

    2013-01-01

    The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB).......The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB)....

  13. Adjuvant Therapy for Gallbladder Carcinoma: The Mayo Clinic Experience

    International Nuclear Information System (INIS)

    Gold, Douglas G.; Miller, Robert C.; Haddock, Michael G.; Gunderson, Leonard L.; Quevedo, Fernando; Donohue, John H.; Bhatia, Sumita; Nagorney, David M.

    2009-01-01

    Purpose: To analyze the effect of adjuvant chemoradiotherapy on gallbladder carcinoma. Methods and Materials: We retrospectively reviewed the records from consecutive patients who underwent R0 resection of gallbladder carcinoma between January 1, 1985, and December 31, 2004. Patients had either Stage I (T1-T2N0M0) or Stage II (T3N0M0 or T1-T3N1M0) disease. Patients undergoing adjuvant therapy received 5-fluorouracil chemotherapy concurrently with radiotherapy (median dosage, 50.4 Gy in 28 fractions). Adverse prognostic factors and the effect of adjuvant treatment on overall survival (OS) were evaluated. Results: A total of 73 patients were included in the analysis; of these, 25 received adjuvant chemoradiotherapy. On univariate analysis, no adverse prognostic factors for OS reached statistical significance, but trends were noted for Stage N1 vs. N0 (p = .06), Nx vs. N0 (p = .09), Stage T3 vs. T1-T2 (p = .06), and histologic findings other than adenocarcinoma (p = .13). The median OS for patients receiving adjuvant chemoradiotherapy vs. surgery alone was 4.8 years and 4.2 years, respectively (log-rank test, p = .56). However, a significantly greater percentage of patients receiving adjuvant chemoradiotherapy had Stage II disease (p <.001). In the multivariate Cox model, increasing T and N category and histologic findings other than adenocarcinoma were significant predictors of decreased OS. Additionally, adjuvant chemoradiotherapy was a significant predictor of improved OS after adjusting for these prognostic factors (hazard ratio for death, 0.3; 95% confidence interval, 0.13-0.69; p = .004). Conclusion: After adjusting for the stage parameters and histologic findings, our data suggest that adjuvant chemoradiotherapy might improve OS for patients with gallbladder cancer.

  14. Adjuvant chemotherapy for gastric cancer: Current evidence and future challenges

    OpenAIRE

    Miceli, Rosalba; Tomasello, Gianluca; Bregni, Giacomo; Di Bartolomeo, Maria; Pietrantonio, Filippo

    2014-01-01

    Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients survival is mainly related to stage, with a high proportion of patients with metastatic disease at presentation. Thus, the cure rate largely depend upon surgical resection. Despite the additional, albeit small, benefit of adjuvant chemotherapy has been clearly demonstrated, no general consensus has been reached on the best treatment option. Moreover, the narrow therapeutic index of adjuvant chemoth...

  15. Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant

    OpenAIRE

    Li, Xiangming; Fujio, Masakazu; Imamura, Masakazu; Wu, Douglass; Vasan, Sandhya; Wong, Chi-Huey; Ho, David D.; Tsuji, Moriya

    2010-01-01

    The glycolipid α-galactosylceramide (α-GalCer) has been shown to bind CD1d molecules to activate invariant natural killer T (iNKT) cells, and subsequently induce activation of various immune-competent cells, including dendritic cells, thereby providing a significant adjuvant effect for various vaccines. However, in phase I clinical trials, α-GalCer was shown to display only marginal biological activity. In our search for a glycolipid that can exert more potent stimulatory activity against iNK...

  16. Designing CAF-adjuvanted dry powder vaccines: spray drying preserves the adjuvant activity of CAF01.

    Science.gov (United States)

    Ingvarsson, Pall Thor; Schmidt, Signe Tandrup; Christensen, Dennis; Larsen, Niels Bent; Hinrichs, Wouter Leonardus Joseph; Andersen, Peter; Rantanen, Jukka; Nielsen, Hanne Mørck; Yang, Mingshi; Foged, Camilla

    2013-05-10

    Dry powder vaccine formulations are highly attractive due to improved storage stability and the possibility for particle engineering, as compared to liquid formulations. However, a prerequisite for formulating vaccines into dry formulations is that their physicochemical and adjuvant properties remain unchanged upon rehydration. Thus, we have identified and optimized the parameters of importance for the design of a spray dried powder formulation of the cationic liposomal adjuvant formulation 01 (CAF01) composed of dimethyldioctadecylammonium (DDA) bromide and trehalose 6,6'-dibehenate (TDB) via spray drying. The optimal excipient to stabilize CAF01 during spray drying and for the design of nanocomposite microparticles was identified among mannitol, lactose and trehalose. Trehalose and lactose were promising stabilizers with respect to preserving liposome size, as compared to mannitol. Trehalose and lactose were in the glassy state upon co-spray drying with the liposomes, whereas mannitol appeared crystalline, suggesting that the ability of the stabilizer to form a glassy matrix around the liposomes is one of the prerequisites for stabilization. Systematic studies on the effect of process parameters suggested that a fast drying rate is essential to avoid phase separation and lipid accumulation at the surface of the microparticles during spray drying. Finally, immunization studies in mice with CAF01 in combination with the tuberculosis antigen Ag85B-ESAT6-Rv2660c (H56) demonstrated that spray drying of CAF01 with trehalose under optimal processing conditions resulted in the preservation of the adjuvant activity in vivo. These data demonstrate the importance of liposome stabilization via optimization of formulation and processing conditions in the engineering of dry powder liposome formulations. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Adjuvant therapy for ampullary carcinomas: The Mayo Clinic experience

    International Nuclear Information System (INIS)

    Bhatia, Sumita; Miller, Robert C.; Haddock, Michael G.; Donohue, John H.; Krishnan, Sunil

    2006-01-01

    Purpose: To determine the effects of adjuvant radiotherapy and chemotherapy for carcinoma of the ampulla of Vater. Methods and Materials: We retrospectively reviewed the records of 125 patients who underwent definitive surgery for carcinomas involving the ampulla of Vater between April 1977 and February 2005 and who survived more than 50 days after surgery. Twenty-nine of the patients also received adjuvant radiotherapy (median dose, 50.4 Gy in 28 fractions) with concurrent 5-fluorouracil chemotherapy. Adverse prognostic factors were investigated, and overall survival (OS) and local and distant failure were estimated. Results: Adverse prognostic factors for decreased OS by univariate analysis included lymph node (LN) involvement, locally advanced tumors (T3/T4), and poor histologic grade. By multivariate analysis, positive LN status (p = 0.02) alone was associated with decreased OS. The addition of adjuvant radiotherapy and chemotherapy improved OS for patients with positive LN (p = 0.01). Median survival for positive LN patients receiving adjuvant therapy was 3.4 years, vs. 1.6 years for those with surgery alone. Conclusions: The addition of adjuvant radiotherapy and 5-fluorouracil chemotherapy may improve OS in patients with LN involvement. The effect of adjuvant therapy on outcomes for patients with poor histologic grade or T3/T4 tumors without LN involvement could not be assessed

  18. Cationic liposomes formulated with synthetic mycobacterial cordfactor (CAF01: a versatile adjuvant for vaccines with different immunological requirements.

    Directory of Open Access Journals (Sweden)

    Else Marie Agger

    Full Text Available 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.

  19. The vaccine adjuvant alum promotes IL-10 production that suppresses Th1 responses.

    Science.gov (United States)

    Oleszycka, Ewa; McCluskey, Sean; Sharp, Fiona A; Muñoz-Wolf, Natalia; Hams, Emily; Gorman, Aoife L; Fallon, Padraic G; Lavelle, Ed C

    2018-04-01

    The effectiveness of many vaccines licensed for clinical use relates to the induction of neutralising antibodies, facilitated by the inclusion of vaccine adjuvants, particularly alum. However, the ability of alum to preferentially promote humoral rather than cellular, particularly Th1-type responses, is not well understood. We demonstrate that alum activates immunosuppressive mechanisms following vaccination, which limit its capacity to induce Th1 responses. One of the key cytokines limiting excessive immune responses is IL-10. Injection of alum primed draining lymph node cells for enhanced IL-10 secretion ex vivo. Moreover, at the site of injection, macrophages and dendritic cells were key sources of IL-10 expression. Alum strongly enhanced the transcription and secretion of IL-10 by macrophages and dendritic cells. The absence of IL-10 signalling did not compromise alum-induced cell infiltration into the site of injection, but resulted in enhanced antigen-specific Th1 responses after vaccination. In contrast to its decisive regulatory role in regulating Th1 responses, there was no significant change in antigen-specific IgG1 antibody production following vaccination with alum in IL-10-deficient mice. Overall, these findings indicate that injection of alum promotes IL-10, which can block Th1 responses and may explain the poor efficacy of alum as an adjuvant for inducing protective Th1 immunity. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Vitamin E and N-Acetylcysteine as Antioxidant Adjuvant Therapy in Children with Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Youssef Al-Tonbary

    2009-01-01

    Full Text Available Although cancer therapies have experienced great success nowadays, yet the associated toxic response and free radicals formation have resulted in significant number of treatment-induced deaths rather than disease-induced fatalities. Complications of chemotherapy have forced physicians to study antioxidant use as adjunctive treatment in cancer. This study aimed to evaluate the antioxidant role of vitamin E and N-acetyl cysteine (NAC in overcoming treatment-induced toxicity in acute lymphoblastic leukaemia (ALL during the intensive period of chemo-/radiotherapy, almost the first two months of treatment. Forty children newly diagnosed with ALL were enrolled in this study. Twenty children (group I have taken vitamin E and NAC supplementations with chemotherapy and the other twenty children (group II have not taken any adjuvant antioxidant therapy. They were evaluated clinically for the occurrence of complications and by the laboratory parameters (blood levels of glutathione peroxidase (Glu.PX antioxidant enzyme, malondialdehyde (MDA, tumor necrosis factor- (TNF-, liver enzymes, and bone marrow picture. Results revealed reduced chemotherapy and radiotherapy toxicity as evidenced by decreasing level of MDA, increasing level of Glu.Px and decreased occurrence of toxic hepatitis, haematological complications, and need for blood and platelet transfusions in group I compared to group II. We can conclude that vitamin E and NAC have been shown to be effective as antioxidant adjuvant therapy in children with ALL to reduce chemo-/radiotherapy-related toxicities during the initial period of treatment.

  1. No adjuvant effect of Bacillus thuringiensis-maize on allergic responses in mice.

    Directory of Open Access Journals (Sweden)

    Daniela Reiner

    Full Text Available Genetically modified (GM foods are evaluated carefully for their ability to induce allergic disease. However, few studies have tested the capacity of a GM food to act as an adjuvant, i.e. influencing allergic responses to other unrelated allergens at acute onset and in individuals with pre-existing allergy. We sought to evaluate the effect of short-term feeding of GM Bacillus thuringiensis (Bt-maize (MON810 on the initiation and relapse of allergic asthma in mice. BALB/c mice were provided a diet containing 33% GM or non-GM maize for up to 34 days either before ovalbumin (OVA-induced experimental allergic asthma or disease relapse in mice with pre-existing allergy. We observed that GM-maize feeding did not affect OVA-induced eosinophilic airway and lung inflammation, mucus hypersecretion or OVA-specific antibody production at initiation or relapse of allergic asthma. There was no adjuvant effect upon GM-maize consumption on the onset or severity of allergic responses in a mouse model of allergic asthma.

  2. Vitamin E and N-Acetylcysteine as Antioxidant Adjuvant Therapy in Children with Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Al-Tonbary, Youssef; Al-Haggar, Mohammad; EL-Ashry, Rasha; EL-Dakroory, Sahar; Azzam, Hanan; Fouda, Ashraf

    2009-01-01

    Although cancer therapies have experienced great success nowadays, yet the associated toxic response and free radicals formation have resulted in significant number of treatment-induced deaths rather than disease-induced fatalities. Complications of chemotherapy have forced physicians to study antioxidant use as adjunctive treatment in cancer. This study aimed to evaluate the antioxidant role of vitamin E and N-acetyl cysteine (NAC) in overcoming treatment-induced toxicity in acute lymphoblastic leukaemia (ALL) during the intensive period of chemo-/radiotherapy, almost the first two months of treatment. Forty children newly diagnosed with ALL were enrolled in this study. Twenty children (group I) have taken vitamin E and NAC supplementations with chemotherapy and the other twenty children (group II) have not taken any adjuvant antioxidant therapy. They were evaluated clinically for the occurrence of complications and by the laboratory parameters (blood levels of glutathione peroxidase (Glu.PX) antioxidant enzyme, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), liver enzymes, and bone marrow picture). Results revealed reduced chemotherapy and radiotherapy toxicity as evidenced by decreasing level of MDA, increasing level of Glu.Px and decreased occurrence of toxic hepatitis, haematological complications, and need for blood and platelet transfusions in group I compared to group II. We can conclude that vitamin E and NAC have been shown to be effective as antioxidant adjuvant therapy in children with ALL to reduce chemo-/radiotherapy-related toxicities during the initial period of treatment. PMID:19960046

  3. Risk of endocrine pancreatic insufficiency in patients receiving adjuvant chemoradiation for resected gastric cancer

    International Nuclear Information System (INIS)

    Gemici, Cengiz; Sargin, Mehmet; Uygur-Bayramicli, Oya; Mayadagli, Alpaslan; Yaprak, Gokhan; Dabak, Resat; Kocak, Mihriban

    2013-01-01

    Background: Adjuvant radiotherapy combined with 5-fluorouracil based chemotherapy has become the new standard after curative resection in high risk gastric cancer. Beside many complications due to surgery, the addition of chemotherapy and radiotherapy as adjuvant treatment may lead to both acute and late toxicities. Pancreatic tissue irradiation during this adjuvant treatment because of incidental and unavoidable inclusion of the organ within the radiation field may affect exocrine and endocrine functions of the organ. Materials and methods: Fifty-three patients with gastric adenocarcinoma were evaluated for adjuvant chemoradiotherapy after surgery. While 37 out of 53 patients were treated postoperatively due to either serosal or adjacent organ or lymph node involvement, 16 patients without these risk factors were followed up regularly without any additional treatment and they served as the control group. Fasting blood glucose (FBG), hemoglobin A1c (HBA1c), insulin and C-peptide levels were measured in the control and study groups after the surgery and 6 months and 1 year later. Results: At the baseline there was no difference in FBG, HbA1c, C-peptide and insulin levels between the control and the study groups. At the end of the study there was a statistically significant decline in insulin and C-peptide levels in the study group, (7.5 ± 6.0 vs 4.5 ± 4.4 IU/L, p: 0.002 and 2.3 ± 0.9 vs 1.56 ± 0.9 ng/ml, p: 0.001) respectively. Conclusions: Adjuvant radiotherapy in gastric cancer leads to a decrease in beta cell function and insulin secretion capacity of the pancreas with possible diabetes risk. Radiation-induced pancreatic injury and late effects of radiation on normal pancreatic tissue are unknown, but pancreas is more sensitive to radiation than known. This organ should be studied extensively in order to determine the tolerance doses and it should be contoured during abdominal radiotherapy planning as an organ at risk

  4. Risk of endocrine pancreatic insufficiency in patients receiving adjuvant chemoradiation for resected gastric cancer.

    Science.gov (United States)

    Gemici, Cengiz; Sargin, Mehmet; Uygur-Bayramicli, Oya; Mayadagli, Alpaslan; Yaprak, Gokhan; Dabak, Resat; Kocak, Mihriban

    2013-05-01

    Adjuvant radiotherapy combined with 5-fluorouracil based chemotherapy has become the new standard after curative resection in high risk gastric cancer. Beside many complications due to surgery, the addition of chemotherapy and radiotherapy as adjuvant treatment may lead to both acute and late toxicities. Pancreatic tissue irradiation during this adjuvant treatment because of incidental and unavoidable inclusion of the organ within the radiation field may affect exocrine and endocrine functions of the organ. Fifty-three patients with gastric adenocarcinoma were evaluated for adjuvant chemoradiotherapy after surgery. While 37 out of 53 patients were treated postoperatively due to either serosal or adjacent organ or lymph node involvement, 16 patients without these risk factors were followed up regularly without any additional treatment and they served as the control group. Fasting blood glucose (FBG), hemoglobin A1c (HBA1c), insulin and C-peptide levels were measured in the control and study groups after the surgery and 6 months and 1 year later. At the baseline there was no difference in FBG, HbA1c, C-peptide and insulin levels between the control and the study groups. At the end of the study there was a statistically significant decline in insulin and C-peptide levels in the study group, (7.5 ± 6.0 vs 4.5 ± 4.4 IU/L, p: 0.002 and 2.3 ± 0.9 vs 1.56 ± 0.9 ng/ml, p: 0.001) respectively. Adjuvant radiotherapy in gastric cancer leads to a decrease in beta cell function and insulin secretion capacity of the pancreas with possible diabetes risk. Radiation-induced pancreatic injury and late effects of radiation on normal pancreatic tissue are unknown, but pancreas is more sensitive to radiation than known. This organ should be studied extensively in order to determine the tolerance doses and it should be contoured during abdominal radiotherapy planning as an organ at risk. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants.

    Science.gov (United States)

    Hanson, Melissa C; Crespo, Monica P; Abraham, Wuhbet; Moynihan, Kelly D; Szeto, Gregory L; Chen, Stephanie H; Melo, Mariane B; Mueller, Stefanie; Irvine, Darrell J

    2015-06-01

    Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.

  6. Adjuvant Chemoradiation Therapy for Pancreatic Adenocarcinoma: Who Really Benefits?

    Science.gov (United States)

    Merchant, Nipun B; Rymer, Jennifer; Koehler, Elizabeth AS; Ayers, G Daniel; Castellanos, Jason; Kooby, David A; Weber, Sharon H; Cho, Clifford S; Schmidt, C Max; Nakeeb, Atilla; Matos, Jesus M; Scoggins, Charles R; Martin, Robert CG; Kim, Hong Jin; Ahmad, Syed A; Chu, Carrie K; McClaine, Rebecca; Bednarski, Brian K; Staley, Charles A; Sharp, Kenneth; Parikh, Alexander A

    2014-01-01

    BACKGROUND The role of adjuvant chemoradiation therapy (CRT) in pancreatic cancer remains controversial. The primary aim of this study was to determine if CRT improved survival in patients with resected pancreatic cancer in a large, multiinstitutional cohort of patients. STUDY DESIGN Patients undergoing resection for pancreatic adenocarcinoma from seven academic medical institutions were included. Exclusion criteria included patients with T4 or M1 disease, R2 resection margin, preoperative therapy, chemotherapy alone, or if adjuvant therapy status was unknown. RESULTS There were 747 patients included in the initial evaluation. Primary analysis was performed between patients that had surgery alone (n = 374) and those receiving adjuvant CRT (n = 299). Median followup time was 12.2 months and 14.5 months for survivors. Median overall survival for patients receiving adjuvant CRT was significantly longer than for those undergoing operation alone (20.0 months versus 14.5 months, p = 0.001). On subset and multivariate analysis, adjuvant CRT demonstrated a significant survival advantage only among patients who had lymph node (LN)-positive disease (hazard ratio 0.477, 95% CI 0.357 to 0.638) and not for LN-negative patients (hazard ratio 0.810, 95% CI 0.556 to 1.181). Disease-free survival in patients with LN-negative disease who received adjuvant CRT was significantly worse than in patients who had surgery alone (14.5 months versus 18.6 months, p = 0.034). CONCLUSIONS This large multiinstitutional study emphasizes the importance of analyzing subsets of patients with pancreas adenocarcinoma who have LN metastasis. Benefit of adjuvant CRT is seen only in patients with LN-positive disease, regardless of resection margin status. CRT in patients with LN-negative disease may contribute to reduced disease-free survival. PMID:19476845

  7. Barbatiman and chitosan creams as adjuvants in rabbit skin wound healing

    Directory of Open Access Journals (Sweden)

    Caroline Rocha de Oliveira Lima

    2016-06-01

    Full Text Available In this study, 5% barbatiman and 5% chitosan creams were evaluated as adjuvants in the tissue repair process by secondary intention of rabbit’s skin wounds. Four equidistant wounds were induced in the dorsal skin of 20 adult male rabbits, which were submitted to healing by secondary intention and treated with 5% chitosan cream (QC, n=5, 5% barbatiman cream (BC, n=5, 2% allantoin cream (n=5, and base cream (n=5. The creams were applied with the aid of disposable spatulas after washing the wounds. The wounds were daily analyzed by clinical examination for 21 days and histological analyses were performed on the 3rd, 14th, and 21st day after induction. The microscopic evaluation of the wounds of all groups showed macroscopic features of the healing process at different time intervals. The QC and BC treatments helped in the skin repair process in rabbits when compared to the other two treatments. They induced fibroblast activation and early collagen deposition, and modulated re-epithelialization and neovascularization. Thus, it was concluded that BC and QC are efficient and economically feasible as adjuvants in the healing process of skin wounds in rabbits.

  8. The Anti-Inflammatory Activity of Toonaciliatin K against Adjuvant Arthritis

    Directory of Open Access Journals (Sweden)

    HaiXing Gou

    2017-01-01

    Full Text Available Toonaciliatin K is a natural limonoid purified from the Toona ciliata Roem. var. ciliata (Meliaceae. This study is to reveal the inflammatory suppression effect of toonaciliatin K and further the intrinsic mechanism. Firstly, anti-inflammatory effect of toonaciliatin K was evaluated in lipopolysaccharide- (LPS- induced RAW264.7 cells. RT-PCR results indicated that the mRNA expressions of TNF-α, IL-6, and IL-1β were downregulated by toonaciliatin K. The toonaciliatin K inhibited TNF-α, IL-6, and IL-1β levels stimulated by LPS. Furthermore, LPS elicited the excess iNOS and COX-2 mRNA and protein production and toonaciliatin K attenuated the excess production. Western blot assay demonstrated that MAPK and NF-κB signaling pathways play critical roles in the toonaciliatin K’s anti-inflammatory activity. Secondly, toonaciliatin K inhibited carrageenan-induced paw edema in rats. Thirdly, toonaciliatin K alleviated the paw swelling and improved arthritis clinical scores in the adjuvant arthritis rats. Toonaciliatin K decreased the proinflammatory cytokines levels and Mankin scores in adjuvant arthritis rats. The HE staining, safranin O-fast green, and toluidine blue staining results demonstrated that toonaciliatin K alleviated the histological changes of paw, for example, pannus formation, focal loss of cartilage, bone erosion, and presence of extra-articular inflammation. Hence, toonaciliatin K is a promising agent for treatment of arthritis.

  9. Poly-ϵ-caprolactone/chitosan nanoparticles provide strong adjuvant effect for hepatitis B antigen.

    Science.gov (United States)

    Jesus, Sandra; Soares, Edna; Borchard, Gerrit; Borges, Olga

    2017-10-01

    This work aims to investigate the adjuvant effect of poly-ϵ-caprolactone/chitosan nanoparticles (NPs) for hepatitis B surface antigen (HBsAg) and the plasmid DNA encoding HBsAg (pRC/CMV-HBs). Both antigens were adsorbed onto preformed NPs. Vaccination studies were performed in C57BL/6 mice. Transfection efficiency was investigated in A549 cell line. HBsAg-adsorbed NPs generated strong anti-HBsAg IgG titers, mainly of IgG1 isotype, and induced antigen-specific IFN-γ and IL-17 secretion by spleen cells. The addition of pRC/CMV-HBs to the HBsAg-adsorbed NPs inhibited IL-17 secretion but had minor effect on IFN-γ levels. Lastly, pRC/CMV-HBs-loaded NPs generated a weak serum antibody response. Poly-ϵ-caprolactone/chitosan NPs provide a strong humoral adjuvant effect for HBsAg and induce a Th1/Th17-mediated cellular immune responses worth explore for hepatitis B virus vaccination.

  10. Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition.

    Science.gov (United States)

    Vaccari, Monica; Gordon, Shari N; Fourati, Slim; Schifanella, Luca; Liyanage, Namal P M; Cameron, Mark; Keele, Brandon F; Shen, Xiaoying; Tomaras, Georgia D; Billings, Erik; Rao, Mangala; Chung, Amy W; Dowell, Karen G; Bailey-Kellogg, Chris; Brown, Eric P; Ackerman, Margaret E; Vargas-Inchaustegui, Diego A; Whitney, Stephen; Doster, Melvin N; Binello, Nicolo; Pegu, Poonam; Montefiori, David C; Foulds, Kathryn; Quinn, David S; Donaldson, Mitzi; Liang, Frank; Loré, Karin; Roederer, Mario; Koup, Richard A; McDermott, Adrian; Ma, Zhong-Min; Miller, Christopher J; Phan, Tran B; Forthal, Donald N; Blackburn, Matthew; Caccuri, Francesca; Bissa, Massimiliano; Ferrari, Guido; Kalyanaraman, Vaniambadi; Ferrari, Maria G; Thompson, DeVon; Robert-Guroff, Marjorie; Ratto-Kim, Silvia; Kim, Jerome H; Michael, Nelson L; Phogat, Sanjay; Barnett, Susan W; Tartaglia, Jim; Venzon, David; Stablein, Donald M; Alter, Galit; Sekaly, Rafick-Pierre; Franchini, Genoveffa

    2016-07-01

    A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.

  11. Predictive markers of safety and immunogenicity of adjuvanted vaccines.

    Science.gov (United States)

    Mastelic, Beatris; Garçon, Nathalie; Del Giudice, Giuseppe; Golding, Hana; Gruber, Marion; Neels, Pieter; Fritzell, Bernard

    2013-11-01

    Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/. Copyright © 2013. Published by Elsevier Ltd.. All rights reserved.

  12. Adjuvant chemotherapy for gastric cancer: Current evidence and future challenges

    Science.gov (United States)

    Miceli, Rosalba; Tomasello, Gianluca; Bregni, Giacomo; Di Bartolomeo, Maria; Pietrantonio, Filippo

    2014-01-01

    Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients survival is mainly related to stage, with a high proportion of patients with metastatic disease at presentation. Thus, the cure rate largely depend upon surgical resection. Despite the additional, albeit small, benefit of adjuvant chemotherapy has been clearly demonstrated, no general consensus has been reached on the best treatment option. Moreover, the narrow therapeutic index of adjuvant chemotherapy (i.e., limited survival benefit with considerable toxicity) requires a careful assessment of expected risks and benefits for individual patients. Treatment choices vary widely based on the different geographic areas, with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States. In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses. The most recent patient-level meta-analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery; the same Authors also showed that disease-free survival may be used as a surrogate end-point for overall survival. We finally discuss future research issues such as the need of economic evaluations, development of prognostic or predictive biomarkers, and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment. PMID:24782604

  13. Environmental adjuvants, apoptosis and the censorship over autoimmunity.

    Science.gov (United States)

    Rovere-Querini, Patrizia; Manfredi, Angelo A; Sabbadini, Maria Grazia

    2005-11-01

    Alterations during apoptosis lead to the activation of autoreactive T cells and the production of autoantibodies. This article discusses the pathogenic potential of cells dying in vivo, dissecting the role of signals that favor immune responses (adjuvants) and the influence of genetic backgrounds. Diverse factors determine whether apoptosis leads or not to a self-sustaining, clinically apparent autoimmune disease. The in vivo accumulation of uncleared dying cells per se is not sufficient to cause disease. However, dying cells are antigenic and their complementation with immune adjuvants causes lethal diseases in predisposed lupus-prone animals. At least some adjuvant signals directly target the function and the activation state of antigen presenting cells. Several laboratories are aggressively pursuing the molecular identification of endogenous adjuvants. Sodium monourate and the high mobility group B1 protein (HMGB1) are, among those identified so far, well known to rheumatologists. However, even the complementation of apoptotic cells with potent adjuvant signals fail to cause clinical autoimmunity in most strains: autoantibodies generated are transient, do not undergo to epitope/spreading and do not cause disease. Novel tools for drug development will derive from the molecular identification of the constraints that prevent autoimmunity in normal subjects.

  14. Novel adjuvants & delivery vehicles for vaccines development: a road ahead.

    Science.gov (United States)

    Mohan, Teena; Verma, Priyanka; Rao, D Nageswara

    2013-11-01

    The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism vaccines. One can improve the quality of vaccine production by incorporating immunomodulators or adjuvants with modified delivery vehicles viz. liposomes, immune stimulating complexes (ISCOMs), micro/nanospheres apart from alum, being used as gold standard. Adjuvants are used to augment the effect of a vaccine by stimulating the immune system to respond to the vaccine, more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionary conserved molecules which include lipopolysaccharides (LPS), components of bacterial cell wall, endocytosed nucleic acids such as dsRNA, ssDNA and unmethylated CpG dinucleotide containing DNA. This review provides information on various vaccine adjuvants and delivery vehicles being developed to date. From literature, it seems that the humoral immune responses have been observed for most adjuvants and delivery platforms while viral-vector, ISCOMs and Montanides have shown cytotoxic T-cell response in the clinical trials. MF59 and MPL® have elicited Th1 responses, and virus-like particles (VLPs), non-degradable nanoparticle and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical success reported for intranasal delivery of viral-vectors and proteosomes and oral delivery of VLP vaccines.

  15. Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women

    DEFF Research Database (Denmark)

    Petäjä, T; Pedersen, Court; Poder, A

    2011-01-01

    Vaccination against oncogenic human papillomavirus (HPV) types is one key intervention for cervical cancer prevention. This follow-up study assessed the persistence of the systemic and mucosal immune responses together with the safety profile of the HPV-16/18 AS04-adjuvanted vaccine administered...... of transudation or exudation of serum IgG antibodies through the cervical epithelium. The HPV-16/18 AS04-adjuvanted vaccine had a clinically acceptable safety profile. In conclusion, this follow-up study shows that the HPV-16/18 AS04-adjuvanted vaccine administered to preteen/adolescents girls and young women...... induces long-term systemic and mucosal immune response and has a clinically acceptable safety profile up to four years after the first vaccine dose....

  16. Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women

    DEFF Research Database (Denmark)

    Petäjä, T; Pedersen, C; Andersen, Anne Poder

    2010-01-01

    Vaccination against oncogenic human papillomavirus (HPV) types is one key intervention for cervical cancer prevention. This follow-up study assessed the persistence of the systemic and mucosal immune responses together with the safety profile of the HPV-16/18 AS04-adjuvanted vaccine administered...... of transudation or exudation of serum IgG antibodies through the cervical epithelium. The HPV-16/18 AS04-adjuvanted vaccine had a clinically acceptable safety profile. In conclusion, this follow-up study shows that the HPV-16/18 AS04-adjuvanted vaccine administered to preteen/adolescents girls and young women...... induces long-term systemic and mucosal immune response and has a clinically acceptable safety profile up to four years after the first vaccine dose....

  17. The Carbomer-Lecithin Adjuvant Adjuplex Has Potent Immunoactivating Properties and Elicits Protective Adaptive Immunity against Influenza Virus Challenge in Mice

    Science.gov (United States)

    Wegmann, Frank; Moghaddam, Amin E.; Schiffner, Torben; Gartlan, Kate H.; Powell, Timothy J.; Russell, Rebecca A.; Baart, Matthijs; Carrow, Emily W.

    2015-01-01

    The continued discovery and development of adjuvants for vaccine formulation are important to safely increase potency and/or reduce the antigen doses of existing vaccines and tailor the adaptive immune response to newly developed vaccines. Adjuplex is a novel adjuvant platform based on a purified lecithin and carbomer homopolymer. Here, we analyzed the adjuvant activity of Adjuplex in mice for the soluble hemagglutinin (HA) glycoprotein of influenza A virus. The titration of Adjuplex revealed an optimal dose of 1% for immunogenicity, eliciting high titers of HA-specific IgG but inducing no significant weight loss. At this dose, Adjuplex completely protected mice from an otherwise lethal influenza virus challenge and was at least as effective as the adjuvants monophosphoryl lipid A (MPL) and alum in preventing disease. Adjuplex elicited balanced Th1-/Th2-type immune responses with accompanying cytokines and triggered antigen-specific CD8+ T-cell proliferation. The use of the peritoneal inflammation model revealed that Adjuplex recruited dendritic cells (DCs), monocytes, and neutrophils in the context of innate cytokine and chemokine secretion. Adjuplex neither triggered classical maturation of DCs nor activated a pathogen recognition receptor (PRR)-expressing NF-κB reporter cell line, suggesting a mechanism of action different from that reported for classical pathogen-associated molecular pattern (PAMP)-activated innate immunity. Taken together, these data reveal Adjuplex to be a potent and well-tolerated adjuvant with application for subunit vaccines. PMID:26135973

  18. The role of MPL and imiquimod adjuvants in enhancement of immune response and protection in BALB/c mice immunized with soluble Leishmania antigen (SLA) encapsulated in nanoliposome.

    Science.gov (United States)

    Emami, Tara; Rezayat, Seyed Mahdi; Khamesipour, Ali; Madani, Rasool; Habibi, Gholamreza; Hojatizade, Mansure; Jaafari, Mahmoud Reza

    2018-04-01

    Adjuvants play an essential role in the induction of immunity against leishmaniasis. In this study, monophosphoryl lipid A (MPL) and imiquimod (IMQ) were used as TLR ligands adjuvants to enhance immunogenicity and rate of protection against leishmaniasis. Nanoliposomes containing soluble Leishmania antigens (SLA) and adjuvants were consisted of DSPC, DSPG and Chol prepared by using lipid film method followed by bath sonication. The size of nanoliposomes was around 95 nm and their zeta potential was negative. BALB/c mice were immunized by liposomal formulations of lip/SLA, lip/MPL/SLA, lip/IMQ/SLA, lip/MPL/IMQ/SLA, lip/SLA + lip/IMQ, lip/SLA + lip/MPL, lip/SLA + lip/MPL/IMQ and five controls of SLA, lip/MPL, lip/IMQ, lip/MPL/IMQ and buffer by subcutaneously (SC) injections, three times in 2 weeks intervals. The synergic effect of two adjuvants when they are used in one formulation showed significantly (p MPL and IMQ adjuvants and antigen in nanoliposome carrier could be an appropriate delivery system to induce cellular immunity pathway against leishmaniasis.

  19. Designing CAF-adjuvanted dry powder vaccines: Spray drying preserves the adjuvant activity of CAF01

    DEFF Research Database (Denmark)

    Ingvarsson, Pall Thor; Schmidt, Signe Tandrup; Christensen, Dennis

    2013-01-01

    spray drying. The optimal excipient to stabilize CAF01 during spray drying and for the design of nanocomposite microparticles was identified among mannitol, lactose and trehalose. Trehalose and lactose were promising stabilizers with respect to preserving liposome size, as compared to mannitol...... parameters suggested that a fast drying rate is essential to avoid phase separation and lipid accumulation at the surface of the microparticles during spray drying. Finally, immunization studies in mice with CAF01 in combination with the tuberculosis antigen Ag85B-ESAT6-Rv2660c (H56) demonstrated that spray...... drying of CAF01 with trehalose under optimal processing conditions resulted in the preservation of the adjuvant activity in vivo. These data demonstrate the importance of liposome stabilization via optimization of formulation and processing conditions in the engineering of dry powder liposome...

  20. Some Aspects Of Adjuvant Treatment Of Colorectal Cancer

    International Nuclear Information System (INIS)

    Hlavata, Z.

    2008-01-01

    Colorectal cancer is one of the most common cancers in Europe and in North America. Cornerstone of the treatment of localized colorectal cancer is surgical resection followed by chemotherapy or radio-chemotherapy in indicated cases. For patients with Stage III colon cancer recent data have shown efficacy through the combining fluorouracil-based chemotherapy with oxaliplatin into adjuvant treatment program. For patients with Stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at high risk for disease recurrence. Current randomized clinical trials in the adjuvant therapy of colorectal cancer are examining the value of adding agents known to be active in metastatic disease, including those that modify specific molecular targets. (author)

  1. Cognitive function after adjuvant treatment for early breast cancer

    DEFF Research Database (Denmark)

    Debess, Jeanne; Riis, Jens Østergaard; Engebjerg, Malene Cramer

    2010-01-01

    The purpose of this study was to examine cognitive function in patients with early breast cancer before and after adjuvant chemotherapy or 6 months of tamoxifen. We performed a population-based study in the county of North Jutland, Denmark, including 120 women aged ... chemotherapy with seven cycles of cyclophosphamide, epirubicin and fluoruracil or adjuvant tamoxifen for 6 months for early breast cancer from 2004 to 2006. They were compared with an aged-matched group of 208 women without previous cancer selected randomly from the same population. Data were collected before...... themselves as impaired at 6 months. Our results do not support that adjuvant chemotherapy is associated with cognitive side effects in breast cancer patients....

  2. Production, purification and immunogenicity of recombinant Ebola virus proteins - A comparison of Freund's adjuvant and adjuvant system 03.

    Science.gov (United States)

    Melén, Krister; Kakkola, Laura; He, Felix; Airenne, Kari; Vapalahti, Olli; Karlberg, Helen; Mirazimi, Ali; Julkunen, Ilkka

    2017-04-01

    There is an urgent need for Ebola virus (EBOV) proteins, EBOV-specific antibodies and recombinant antigens to be used in diagnostics and as potential vaccine candidates. Our objective was to produce and purify recombinant proteins for immunological assays and for the production of polyclonal EBOV specific antibodies. In addition, a limited comparison of the adjuvant effects of Freund's complete adjuvant (FCA) and adjuvant system 03 (AS03) was carried out. Recombinant EBOV GST-VP24, -VP30, -VP35, -VP40 and -NP were produced in E. coli and purified with affinity chromatography followed by preparative gel electrophoresis. Recombinant EBOV GP-His was produced in Sf9 insect cells and purified by preparative gel electrophoresis. To compare the adjuvant effect of FCA and AS03, 12 rabbits were immunized four times with one of the six recombinant EBOV proteins using FCA or AS03. In addition, three guinea pigs were immunized with EBOV VP24 using FCA. With the exception of sera from two rabbits immunized with GST-VP24, the antisera against all other EBOV proteins showed very high and specific antibody responses after three to four immunizations. The adjuvant effect of AS03 was comparable to that of FCA. The produced antibodies recognized the corresponding EBOV proteins in wild type EBOV-infected cells. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. A well-tolerated grass pollen-specific allergy vaccine containing a novel adjuvant, monophosphoryl lipid A, reduces allergic symptoms after only four preseasonal injections.

    Science.gov (United States)

    Drachenberg, K J; Wheeler, A W; Stuebner, P; Horak, F

    2001-06-01

    We present data showing that a Th1-inducing adjuvant can reduce the number of injections required for allergy vaccination. Allergy vaccination is the only treatment for type 1 hypersensitivity that can alter the underlying disease process. A switch of specific T-cell activity from Th2 >Th1 to Th1 >Th2 is believed to be an important change seen after long-term vaccination therapy. An immunologic adjuvant that enhances such a switch could be used to reduce the number of injections required. This would improve compliance with the treatment and provide pharmacoeconomic advantages. Such an adjuvant is 3-deacylated monophosphoryl lipid A (MPL adjuvant, Corixa). A multicentre, placebo-controlled, randomized, double-blind clinical study was performed with a new standardized allergy vaccine comprising a tyrosine-adsorbed glutaraldehyde-modified grass pollen extract containing MPL adjuvant. Four subcutaneous injections of the active product were given preseasonally to 81 grass pollen-sensitive subjects, and 60 received placebo injections (tyrosine alone). Diary cards were used to record symptoms and medication taken during approximately 30 days of the grass pollen season. There was a statistical advantage in favour of the active treatment for nasal (P = 0.016) and ocular (P = 0.003) symptoms and combined symptom and medication scores (P=0.013). Titrated skin prick testing revealed a significant reduction of skin sensitivity in the active group compared to placebo (P = 0.04). Grass-pollen-specific IgG antibody was raised by active treatment (P vaccine, incorporating a Th1-inducing adjuvant, MPL, was efficacious and after only four preseasonal injections produced antibody changes normally associated with long injection schedules. This may encourage wider application of allergy vaccination. The vaccine is now available in a number of countries as Pollinex Quattro.

  4. Evaluation of adjuvant activity of fractions derived from Agaricus blazei, when in association with the recombinant LiHyp1 protein, to protect against visceral leishmaniasis.

    Science.gov (United States)

    de Jesus Pereira, Nathália Cristina; Régis, Wiliam César Bento; Costa, Lourena Emanuele; de Oliveira, Jamil Silvano; da Silva, Alanna Gomes; Martins, Vivian Tamietti; Duarte, Mariana Costa; de Souza, José Roberto Rodrigues; Lage, Paula Sousa; Schneider, Mônica Santos; Melo, Maria Norma; Soto, Manuel; Soares, Sandra Aguiar; Tavares, Carlos Alberto Pereira; Chávez-Fumagalli, Miguel Angel; Coelho, Eduardo Antonio Ferraz

    2015-06-01

    The development of effective prophylactic strategies to prevent leishmaniasis has become a high priority. No less important than the choice of an antigen, the association of an appropriate adjuvant is necessary to achieve a successful vaccination, as the majority of the tested antigens contain limited immunogenic properties, and need to be supplemented with immune response adjuvants in order to boost their immunogenicity. However, few effective adjuvants that can be used against leishmaniasis exist on the market today; therefore, it is possible to speculate that the research aiming to identify new adjuvants could be considered relevant. Recently, Agaricus blazei extracts have proved to be useful in enhancing the immune response to DNA vaccines against some diseases. This was based on the Th1 adjuvant activity of the polysaccharide-rich fractions from this mushroom. In this context, the present study evaluated purified fractions derived from Agaricus blazei as Th1 adjuvants through in vitro assays of their immune stimulation of spleen cells derived from naive BALB/c mice. Two of the tested six fractions (namely F2 and F4) were characterized as polysaccharide-rich fractions, and were able to induce high levels of IFN-γ, and low levels of IL-4 and IL-10 in the spleen cells. The efficacy of adjuvant action against L. infantum was evaluated in BALB/c mice, with these fractions being administered together with a recombinant antigen, LiHyp1, which was previously evaluated as a vaccine candidate, associated with saponin, against visceral leishmaniasis (VL). The associations between LiHyp1/F2 and LiHyp1/F4 were able to induce an in vivo Th1 response, which was primed by high levels of IFN-γ, IL-12, and GM-CSF, by low levels of IL-4 and IL-10; as well as by a predominance of IgG2a antibodies in the vaccinated animals. After infection, the immune profile was maintained, and the vaccines proved to be effective against L. infantum. The immune stimulatory effects in the

  5. Adjuvant treatment and outcomes of stage III endometrial carcinoma

    International Nuclear Information System (INIS)

    Connell, C.; Ludbrook, J.; Davy, M.; Yeoh, E

    2003-01-01

    Surgery with staging using FIGO (1988) classification is accepted management for stage III endometrial carcinoma. The delivery of adjuvant therapy is controversial and tends to be individualised. Retrospective review of stage III endometrial carcinoma patients who underwent radical surgery at the Royal Adelaide and Queen Elizabeth Hospitals from 1984 to 2003 was carried out. Medical records were reviewed for details of patient characteristics, surgery, histopathology, adjuvant therapy and recurrence/survival. Sixty-six patients with a median age of 69 (37-97), had a median follow-up of 26 months (1-188 ). For all stage III patients, the actuarial 5-year disease-free and overall survivals were 50 and 43% respectively. Thirty-five patients received pelvic +/- paraaortic radiotherapy, 5 whole abdominal radiotherapy, 14 vaginal brachytherapy boost, 10 chemotherapy and 13 adjuvant hormones. Forty-six percent of patients recurred in a median time of 13 months (0-95). For these patients, the sites of first recurrence were pelvis in 27%, pelvis and abdomen in 23%, abdomen alone in 13%, distant alone in 27%, distant and abdominal in 7% and all three sites in 3%. On univariate analysis disease-free survival was impacted by; age, grade, parametrial involvement, number of extrauterine sites, lymphovascular invasion, adjuvant radiotherapy to the pelvis alone and postoperative macroscopic residual disease. Lymphovascular invasion, post-operative residual disease and adjuvant pelvic radiotherapy remained significant on multivariate analysis. These outcomes for stage III endometrial carcinoma are comparable to the current literature. Ongoing research is required to establish the most appropriate adjuvant therapy in these high risk patients

  6. Management of Pediatric Myxopapillary Ependymoma: The Role of Adjuvant Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Agbahiwe, Harold C.; Wharam, Moody [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Batra, Sachin [Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Cohen, Kenneth [Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Terezakis, Stephanie A., E-mail: sterezak@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

    2013-02-01

    Introduction: Myxopapillary ependymoma (MPE) is a rare tumor in children. The primary treatment is gross total resection (GTR), with no clearly defined role for adjuvant radiation therapy (RT). Published reports, however, suggest that children with MPE present with a more aggressive disease course. The goal of this study was to assess the role of adjuvant RT in pediatric patients with MPE. Methods: Sixteen patients with MPE seen at Johns Hopkins Hospital (JHH) between November 1984 and December 2010 were retrospectively reviewed. Fifteen of the patients were evaluable with a mean age of 16.8 years (range, 12-21 years). Kaplan-Meier curves and descriptive statistics were used for analysis. Results: All patients received surgery as the initial treatment modality. Surgery consisted of either a GTR or a subtotal resection (STR). The median dose of adjuvant RT was 50.4 Gy (range, 45-54 Gy). All patients receiving RT were treated at the involved site. After a median follow-up of 7.2 years (range, 0.75-26.4 years), all patients were alive with stable disease. Local control at 5 and 10 years was 62.5% and 30%, respectively, for surgery alone versus 100% at both time points for surgery and adjuvant RT. Fifty percent of the patients receiving surgery alone had local failure. All patients receiving STR alone had local failure compared to 33% of patients receiving GTR alone. One patient in the surgery and adjuvant RT group developed a distant site of recurrence 1 year from diagnosis. No late toxicity was reported at last follow-up, and neurologic symptoms either improved or remained stable following surgery with or without RT. Conclusions: Adjuvant RT improved local control compared to surgery alone and should be considered after surgical resection in pediatric patients with MPE.

  7. Clinical development of a novel CD1d-binding NKT cell ligand as a vaccine adjuvant.

    Science.gov (United States)

    Padte, Neal N; Li, Xiangming; Tsuji, Moriya; Vasan, Sandhya

    2011-08-01

    Natural killer T (NKT) cells are known to play a role against certain microbial infections, including malaria and HIV, two major global infectious diseases. Strategies that can harness and amplify the immunotherapeutic potential of NKT cells can serve as powerful tools in the fight against such diseases. 7DW8-5, a novel glycolipid, may be one such tool. The interaction of 7DW8-5 with CD1d molecules induces activation of NKT cells, thereby activating various immune-competent cells including dendritic cells (DCs) to provide a significant adjuvant effect for several vaccines. This review discusses the discovery and characterization of 7DW8-5 and the practical considerations of its preclinical and clinical development as a potential glycolipid adjuvant for candidate malaria and HIV vaccines. Copyright © 2010. Published by Elsevier Inc.

  8. Co-administration of cholera toxin and apple polyphenol extract as a novel and safe mucosal adjuvant strategy.

    Science.gov (United States)

    Yoshino, Naoto; Fujihashi, Kohtaro; Hagiwara, Yukari; Kanno, Hiroyuki; Takahashi, Kiyomi; Kobayashi, Ryoki; Inaba, Noriyuki; Noda, Masatoshi; Sato, Shigehiro

    2009-07-30

    Although native cholera toxin (CT) is an extremely effective adjuvant, its toxicity prevents its use in humans. We report here that apple polyphenol extract (APE), obtained from unripe apples, reduces CT-induced morphological changes and cAMP accumulation. Based upon this finding, we have attempted to design a novel, effective and safe mucosal vaccine by using CT with several dosages of APE as nasal adjuvants. Mice nasally immunized with OVA plus CT and an optimal dosage of APE showed significantly reduced levels of inflammatory responses as well as total and OVA-specific IgE antibodies when compared with mice given without APE. However, levels of both mucosal and systemic OVA-specific antibody responses were maintained. Further, APE significantly down-regulated accumulation of CT in the olfactory nerves and epithelium. In summary, an optimal dosage of APE would take full advantage of mucosal adjuvanticity of native CT without any toxicity for application in humans.

  9. Chemotherapy-related amenorrhea after adjuvant paclitaxel-trastuzumab (APT trial).

    Science.gov (United States)

    Ruddy, Kathryn J; Guo, Hao; Barry, William; Dang, Chau T; Yardley, Denise A; Moy, Beverly; Marcom, P Kelly; Albain, Kathy S; Rugo, Hope S; Ellis, Matthew J; Shapira, Iuliana; Wolff, Antonio C; Carey, Lisa A; Overmoyer, Beth A; Hudis, Clifford; Krop, Ian E; Burstein, Harold J; Winer, Eric P; Partridge, Ann H; Tolaney, Sara M

    2015-06-01

    Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50 % of all premenopausal recipients [1]. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3 cm node-negative HER2 + breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28 %, 95 % CI 18-41 %) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms.

  10. Characterization of the structure and immunostimulatory activity of a vaccine adjuvant, de-O-acylated lipooligosaccharide.

    Directory of Open Access Journals (Sweden)

    Ji Eun Han

    Full Text Available Lipopolysaccharide (LPS is a major component of the outer membrane of Gram-negative bacteria. LPS elicits strong immunopathological responses during bacterial infection, and the lipid A moiety of LPS is responsible for this immunostimulatory activity. Lipid A exerts its biological activity by sending signals via TLR4 present on immune cells, and TLR4 agonists have been a target for vaccine adjuvant. Previously, we demonstrated an adjuvant activity of deacylated lipooligosaccharide (dLOS to viral and bacterial antigens. In this study, we characterized the chemical structure of dLOS and evaluated its immunostimulatory activity on mouse and human immune cells in comparison with monophosphoryl lipid A (MPL. dLOS consists of the R3-type core, a glucosamine disaccharide with two phosphate groups, and two N-linked acyl groups [corrected], and two N-linked acyl groups. dLOS was similar to MPL in induction of cytokine production in mouse peritoneal macrophages, but was a more potent activator in human monocytes and dendritic cells (DCs. Results of an analysis of allogeneic T cell responses revealed that dLOS induces Th1, Th2, and Th17-type immune responses in a dose-dependent manner. The immunostimulatory activities of dLOS were completely abrogated in TLR4(-/- mice, which confirms its TLR4-dependency. These results suggest that in the presence of the core oligosaccharide, O-linked acyl groups of LPS are dispensable for activating the TLR4 signaling pathway. dLOS did not cause any pathological effects or death at 0.25, 0.5, or 1 mg per kg body weight in mice in the acute toxicity tests. This result suggests that dLOS has a low toxicity. dLOS should be considered for further development as a safe and effective adjuvant for human vaccines.

  11. Weak circadian rhythm increases neutropenia risk among breast cancer patients undergoing adjuvant chemotherapy.

    Science.gov (United States)

    Li, Wentao; Kwok, Carol Chi-Hei; Chan, Dominic Chun-Wan; Wang, Feng; Tse, Lap Ah

    2018-04-01

    Severe neutropenia is a common dose-limiting side effect of adjuvant breast cancer chemotherapy. We aimed to test the hypothesis that weak circadian rhythm is associated with an increased risk of neutropenia using a cohort study. We consecutively recruited 193 breast cancer patients who received adjuvant chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel; doxorubicin and cyclophosphamide; docetaxel and cyclophosphamide). Participants wore a wrist actigraph continuously for 168 h at the beginning of chemotherapy. Values of percent rhythm and double amplitude below medians represented weak circadian rhythm. Mesor measured the mean activity level and acrophase symboled the peak time of the rhythm. We used Cox proportional hazard regression model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of grade 4 neutropenia and febrile neutropenia in relation to actigraphy-derived parameters. Low levels of percent rhythm (HR:2.59, 95% CI 1.50-4.72), double amplitude (HR:2.70, 95% CI 1.51-4.85), and mesor (HR: 2.48, 95% CI 1.44-4.29) were positively associated with the risk of grade 4 neutropenia during chemotherapy. Low levels of percent rhythm (HR: 2.41, 95% CI 1.02-5.69) and double amplitude (HR:2.49, 95% CI 1.05-5.90) were also associated with increased risks of febrile neutropenia. The HRs for acrophase were not statistically significant. This study provides the first epidemiological evidence that increased risks of grade 4 neutropenia and febrile neutropenia are associated with weak circadian rhythm among adjuvant breast cancer patients. The results suggest that circadian rhythm might be one potential target for the prevention of chemotherapy-induced neutropenia among cancer patients.

  12. Evaluation of Montanide™ ISA 71 VG adjuvant during profilin vaccination against experimental coccidiosis.

    Directory of Open Access Journals (Sweden)

    Seung I Jang

    Full Text Available Chickens were immunized subcutaneously with an Eimeria recombinant profilin protein plus Montanide™ ISA 70 VG (ISA 70 or Montanide™ 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/ISA 70 vs. profilin alone and by profilin/ISA 71 vs. profilin alone. While immunization with profilin/ISA 70 vs. profilin alone altered the levels of more total transcripts compared with profilin/ISA 71 vs. profilin alone (509 vs. 296, the latter was associated with a greater number of unique biological functions, and a larger number of genes within these functions, compared with the former. Further, canonical pathway analysis identified 10 pathways that were associated with genes encoding the altered transcripts in animals immunized with profilin/ISA 71 vs. profilin alone, compared with only 2 pathways in profilin/ISA 70 vs. profilin alone. Therefore, ISA 71 was selected as a candidate adjuvant in conjunction with profilin vaccination for in vivo disease protection studies. Vaccination with profilin/ISA 71 was associated with greater body weight gain following E. acervulina infection, and decreased parasite fecal shedding after E. maxima infection, compared with profilin alone. Anti-profilin antibody levels were higher in sera of E. maxima- and E. tenella-infected chickens vaccinated with profilin/ISA 71 compared with profilin alone. Finally, the levels of transcripts encoding interferon-γ, interleukin (IL-2, IL-10, and IL-17A were increased in intestinal lymphocytes from E. acervulina-, E. maxima-, and/or E. tenella-infected chickens vaccinated with profilin/ISA 71 compared with profilin alone. None of these effects were seen in chickens injected with ISA 71 alone indicating that the adjuvant was not conferring non-specific immune stimulation. These results suggest that profilin plus ISA 71 augments protective immunity

  13. Evaluation of Montanide™ ISA 71 VG Adjuvant during Profilin Vaccination against Experimental Coccidiosis

    Science.gov (United States)

    Lillehoj, Hyun S.; Lee, Sung Hyen; Lee, Kyung Woo; Bertrand, François; Dupuis, Laurent; Deville, Sébastien; Ben Arous, Juliette; Lillehoj, Erik P.

    2013-01-01

    Chickens were immunized subcutaneously with an Eimeria recombinant profilin protein plus Montanide™ ISA 70 VG (ISA 70) or Montanide™ 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/ISA 70 vs. profilin alone and by profilin/ISA 71 vs. profilin alone. While immunization with profilin/ISA 70 vs. profilin alone altered the levels of more total transcripts compared with profilin/ISA 71 vs. profilin alone (509 vs. 296), the latter was associated with a greater number of unique biological functions, and a larger number of genes within these functions, compared with the former. Further, canonical pathway analysis identified 10 pathways that were associated with genes encoding the altered transcripts in animals immunized with profilin/ISA 71 vs. profilin alone, compared with only 2 pathways in profilin/ISA 70 vs. profilin alone. Therefore, ISA 71 was selected as a candidate adjuvant in conjunction with profilin vaccination for in vivo disease protection studies. Vaccination with profilin/ISA 71 was associated with greater body weight gain following E. acervulina infection, and decreased parasite fecal shedding after E. maxima infection, compared with profilin alone. Anti-profilin antibody levels were higher in sera of E. maxima- and E. tenella-infected chickens vaccinated with profilin/ISA 71 compared with profilin alone. Finally, the levels of transcripts encoding interferon-γ, interleukin (IL)-2, IL-10, and IL-17A were increased in intestinal lymphocytes from E. acervulina-, E. maxima-, and/or E. tenella-infected chickens vaccinated with profilin/ISA 71 compared with profilin alone. None of these effects were seen in chickens injected with ISA 71 alone indicating that the adjuvant was not conferring non-specific immune stimulation. These results suggest that profilin plus ISA 71 augments protective immunity against selective

  14. Potential of Cationic Liposomes as Adjuvants/Delivery Systems for Tuberculosis Subunit Vaccines.

    Science.gov (United States)

    Khademi, Farzad; Taheri, Ramezan Ali; Momtazi-Borojeni, Amir Abbas; Farnoosh, Gholamreza; Johnston, Thomas P; Sahebkar, Amirhossein

    2018-04-27

    The weakness of the BCG vaccine and its highly variable protective efficacy in controlling tuberculosis (TB) in different age groups as well as in different geographic areas has led to intense efforts towards the development and design of novel vaccines. Currently, there are several strategies to develop novel TB vaccines. Each strategy has its advantages and disadvantages. However, the most important of these strategies is the development of subunit vaccines. In recent years, the use of cationic liposome-based vaccines has been considered due to their capacity to elicit strong humoral and cellular immune responses against TB infections. In this review, we aim to evaluate the potential for cationic liposomes to be used as adjuvants/delivery systems for eliciting immune responses against TB subunit vaccines. The present review shows that cationic liposomes have extensive applications either as adjuvants or delivery systems, to promote immune responses against Mycobacterium tuberculosis (Mtb) subunit vaccines. To overcome several limitations of these particles, they were used in combination with other immunostimulatory factors such as TDB, MPL, TDM, and Poly I:C. Cationic liposomes can provide long-term storage of subunit TB vaccines at the injection site, confer strong electrostatic interactions with APCs, potentiate both humoral and cellular (CD4 and CD8) immune responses, and induce a strong memory response by the immune system. Therefore, cationic liposomes can increase the potential of different TB subunit vaccines by serving as adjuvants/delivery systems. These properties suggest the use of cationic liposomes to produce an efficient vaccine against TB infections.

  15. Polymerized serum albumin beads for use as slow-release adjuvants

    International Nuclear Information System (INIS)

    Martin, M.E.D.

    1987-02-01

    Experimental vaccines have been made by covalently bonding virus particles into polymerized rabbit serum albumin beads. Using Nodamura virus as a model antigen, these model vaccines induced specific humoral antibody production, comparable with that achieved using Freund's adjuvants. Virus specific antibodies were also induced when Nodamura virus was covalently attached to the bead surface using different crosslinkers. However, when poliovirus type 2 (Sabin strain) was polymerized into beads, the levels of neutralizing antibodies were insignificant compared with control aqueous vaccines. The synthetic immunostimulator, muramyl dipeptide, was included with bead vaccines in an attempt to potentiate the immune response. Immunostimulation is achieved by a slow release of antigen coinciding with the gradual breakdown of bead structure. Methods used include radio-iodination and radioimmunoassay. 65 figs., 6 tabs., 173 refs

  16. Novel adjuvant based on a proteoliposome-derived cochleate structure containing native lipopolysaccharide as a pathogen-associated molecular pattern.

    Science.gov (United States)

    Pérez, Oliver; Bracho, Gustavo; Lastre, Miriam; Mora, Nestor; del Campo, Judith; Gil, Danay; Zayas, Caridad; Acevedo, Reinaldo; González, Domingo; López, José A; Taboada, Carlos; Turtle, Cameron; Solis, Rosa L

    2004-12-01

    Proteoliposomes (PL) from Neisseria meningitidis B have been widely used as a core antigen for antimeningococcal vaccination. PL contain major outer membrane proteins, LPS and phospholipids, and they induce a strong Th1 immune response, but they have low stability in solution. Attending to the need for new vaccine adjuvants, we developed a highly stable cochleate structure (CS) from PL using a technology that allows easy incorporation of new antigens. We explored the ability of PLCS to activate the immune system and its possible application as an adjuvant for parenteral and mucosal routes. Our results showed that PLCS were able to upregulate the expression of MHC class II and costimulatory molecules on human dendritic cells, as well as being able to stimulate the production of soluble mediators of a Th1 response, such as IL-12 and nitric oxide. High levels of anti-PL IgG were detected in serum after i.m. or mucosal (oral and nasal) administration, but also anti-PL secretory IgA was produced in saliva following nasal delivery. The immune response polarization to a Th1 pattern was confirmed by the induction of IgG2a antibodies, positive delayed type hypersensitivity reactions, and IFN-gamma production by splenocytes from immunized mice. The adjuvant potential was explored using PLCS containing ovalbumin (Ova). PLCS-Ova was able to elicit a substantial increase in anti-Ova IgG compared with Ova alone. In addition, a significant reduction in lesion size was observed in mice immunized with Leishmania major antigens in PLCS after challenge with virulent protozoa, suggesting at least partial modulation of the Th2 environment induced by this parasite. In conclusion, our results support the use of PLCS as a potent Th1 adjuvant for parenteral and mucosal vaccines.

  17. Human innate responses and adjuvant activity of TLR ligands in vivo in mice reconstituted with a human immune system.

    Science.gov (United States)

    Cheng, Liang; Zhang, Zheng; Li, Guangming; Li, Feng; Wang, Li; Zhang, Liguo; Zurawski, Sandra M; Zurawski, Gerard; Levy, Yves; Su, Lishan

    2017-10-27

    TLR ligands (TLR-Ls) represent a class of novel vaccine adjuvants. However, their immunologic effects in humans remain poorly defined in vivo. Using a humanized mouse model with a functional human immune system, we investigated how different TLR-Ls stimulated human innate immune response in vivo and their applications as vaccine adjuvants for enhancing human cellular immune response. We found that splenocytes from humanized mice showed identical responses to various TLR-Ls as human PBMCs in vitro. To our surprise, various TLR-Ls stimulated human cytokines and chemokines differently in vivo compared to that in vitro. For example, CpG-A was most efficient to induce IFN-α production in vitro. In contrast, CpG-B, R848 and Poly I:C stimulated much more IFN-α than CpG-A in vivo. Importantly, the human innate immune response to specific TLR-Ls in humanized mice was different from that reported in C57BL/6 mice, but similar to that reported in nonhuman primates. Furthermore, we found that different TLR-Ls distinctively activated and mobilized human plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs) and monocytes in different organs. Finally, we showed that, as adjuvants, CpG-B, R848 and Poly I:C can all enhance antigen specific CD4 + T cell response, while only R848 and Poly I:C induced CD8 + cytotoxic T cells response to a CD40-targeting HIV vaccine in humanized mice, correlated with their ability to activate human mDCs but not pDCs. We conclude that humanized mice serve as a highly relevant model to evaluate and rank the human immunologic effects of novel adjuvants in vivo prior to testing in humans. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Allergy adjuvant effect of particles from wood smoke and road traffic.

    Science.gov (United States)

    Samuelsen, Mari; Nygaard, Unni Cecilie; Løvik, Martinus

    2008-04-18

    There is growing evidence that in addition to augmenting the severity of asthma and allergic diseases, particulate air pollution also increases the incidence of allergy and asthma. We studied the adjuvant effect of particles from wood smoke and road traffic on the immune response to the allergen ovalbumin (OVA). OVA with and without particles was injected into one hind footpad of Balb/cA mice. All particles together with OVA significantly increased the level of OVA-specific immunoglobulin E (IgE) in serum, compared to groups given OVA or particles alone. Reference diesel exhaust particles (DEP) with OVA induced the highest levels of IgE, whereas no clear difference was observed between particles from road traffic and wood smoke. Road traffic particles collected in the autumn induced higher IgE values with OVA than corresponding particles collected during the winter season when studded tires are used, suggesting that studded tire-generated road pavement particles have less allergy adjuvant activity than exhaust particles. Compared to OVA or particles alone, all particles with OVA increased popliteal lymph node cell numbers, cell proliferation, ex vivo secretion of IL-4 and IL-10 after ConA stimulation, and the expression of several cell surface molecules (CD19, MHC class II, CD86 and CD23). Wood smoke particles with OVA induced somewhat higher cellular responses than road traffic particles, but less than DEP with OVA which seemed to be the most potent particle in inducing cellular as well as antibody responses. Thus, wood smoke particles had about the same capacity to enhance allergic sensitization as road traffic particles, but less than diesel exhaust particles.

  19. Allergy adjuvant effect of particles from wood smoke and road traffic

    International Nuclear Information System (INIS)

    Samuelsen, Mari; Nygaard, Unni Cecilie; Lovik, Martinus

    2008-01-01

    There is growing evidence that in addition to augmenting the severity of asthma and allergic diseases, particulate air pollution also increases the incidence of allergy and asthma. We studied the adjuvant effect of particles from wood smoke and road traffic on the immune response to the allergen ovalbumin (OVA). OVA with and without particles was injected into one hind footpad of Balb/cA mice. All particles together with OVA significantly increased the level of OVA-specific immunoglobulin E (IgE) in serum, compared to groups given OVA or particles alone. Reference diesel exhaust particles (DEP) with OVA induced the highest levels of IgE, whereas no clear difference was observed between particles from road traffic and wood smoke. Road traffic particles collected in the autumn induced higher IgE values with OVA than corresponding particles collected during the winter season when studded tires are used, suggesting that studded tire-generated road pavement particles have less allergy adjuvant activity than exhaust particles. Compared to OVA or particles alone, all particles with OVA increased popliteal lymph node cell numbers, cell proliferation, ex vivo secretion of IL-4 and IL-10 after ConA stimulation, and the expression of several cell surface molecules (CD19, MHC class II, CD86 and CD23). Wood smoke particles with OVA induced somewhat higher cellular responses than road traffic particles, but less than DEP with OVA which seemed to be the most potent particle in inducing cellular as well as antibody responses. Thus, wood smoke particles had about the same capacity to enhance allergic sensitization as road traffic particles, but less than diesel exhaust particles

  20. Long-term heart function after adjuvant epirubicin chemotherapy for breast cancer

    DEFF Research Database (Denmark)

    Appel, Jon M; Zerahn, Bo; Møller, Susanne

    2012-01-01

    Newer studies raise concern that adjuvant anthracycline treatment for breast cancer (BC) causes long-term heart damage. We aimed to examine whether heart failure or impairment could be demonstrated several years after low-dose epirubicin-based adjuvant treatment.......Newer studies raise concern that adjuvant anthracycline treatment for breast cancer (BC) causes long-term heart damage. We aimed to examine whether heart failure or impairment could be demonstrated several years after low-dose epirubicin-based adjuvant treatment....

  1. Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines

    Directory of Open Access Journals (Sweden)

    Masayuki Hayashi

    2017-02-01

    Full Text Available Advax, a delta inulin-derived microparticle, has been developed as an adjuvant for several vaccines. However, its immunological characteristics and potential mechanism of action are yet to be elucidated. Here, we show that Advax behaves as a type-2 adjuvant when combined with influenza split vaccine, a T helper (Th2-type antigen, but behaves as a type-1 adjuvant when combined with influenza inactivated whole virion (WV, a Th1-type antigen. In addition, an adjuvant effect was not observed when Advax-adjuvanted WV vaccine was used to immunize toll-like receptor (TLR 7 knockout mice which are unable to respond to RNA contained in WV antigen. Similarly, no adjuvant effect was seen when Advax was combined with endotoxin-free ovalbumin, a neutral Th0-type antigen. An adjuvant effect was also not seen in tumor necrosis factor (TNF-α knockout mice, and the adjuvant effect required the presences of dendritic cells (DCs and phagocytic macrophages. Therefore, unlike other adjuvants, Advax potentiates the intrinsic or in-built adjuvant property of co-administered antigens. Hence, Advax is a unique class of adjuvant which can potentiate the intrinsic adjuvant feature of the vaccine antigens through a yet to be determined mechanism.

  2. Comparison of adjuvants for immune potentiating properties and side effects in mice

    NARCIS (Netherlands)

    Leenaars, P.P.A.M.; Hendriksen, C.F.M.; Koedam, M.A.; Claassen, I.; Claassen, E.

    1995-01-01

    Four types of adjuvants were evaluated as alternatives to the use of Freund's complete adjuvant in mice. The adjuvants evaluated included a water-in-oil emulsion (Specol), a microorganism (Lactobacillus), preformed immune-stimulating complexes (ISCOM) containing rabies virus glycoprotein and a

  3. Tailorable Trimethyl chitosans as adjuvant for intranasal immunization

    NARCIS (Netherlands)

    Verheul, R.J.

    2010-01-01

    Tailorable Trimethyl Chitosans as Adjuvant for Intranasal Immunization Active vaccination has proven to be the most (cost) effective tool in the fight against infectious diseases. Nowadays, most vaccines are administered via parenteral injection. However, the risk of contaminated needles and need

  4. Benefits of adjuvant chemotherapy in high-grade gliomas.

    Science.gov (United States)

    DeAngelis, Lisa M

    2003-12-01

    The current standard of care for patients with high-grade glioma is resection followed by radiotherapy. Adjuvant chemotherapy is not widely accepted because of the low sensitivity of gliomas to traditional antineoplastic agents, the poor penetration of most drugs across the blood-brain barrier, and the significant systemic toxicity associated with current agents. However, nitrosoureas and, subsequently, temozolomide (Temodar [US], Temodal [international]; Schering-Plough Corporation, Kenilworth, NJ), a novel alkylating agent, cross the blood-brain barrier and have activity against gliomas. Nitrosoureas have been studied in phase III trials in the adjuvant setting. In individual trials, chemotherapy did not increase median survival but did increase the proportion of patients surviving >/=18 months by 15%. Only with large meta-analyses did the addition of chemotherapy achieve a statistically significant improvement in median survival. Currently there is no means of identifying which patients will benefit from adjuvant chemotherapy, but nitrosoureas and temozolomide are well tolerated in most patients, justifying the administration of adjuvant chemotherapy to all newly diagnosed patients with malignant glioma.

  5. Postoperative adjuvant chemotherapy in rectal cancer operated for cure

    DEFF Research Database (Denmark)

    Petersen, Sune Høirup; Harling, Henrik; Kirkeby, Lene Tschemerinsky

    2012-01-01

    Colorectal cancer is one of the most common types of cancer in the Western world. Apart from surgery - which remains the mainstay of treatment for resectable primary tumours - postoperative (i.e., adjuvant) chemotherapy with 5-fluorouracil (5-FU) based regimens is now the standard treatment in Du...

  6. Postoperative adjuvant chemotherapy in rectal cancer operated for cure.

    Science.gov (United States)

    Petersen, Sune Høirup; Harling, Henrik; Kirkeby, Lene Tschemerinsky; Wille-Jørgensen, Peer; Mocellin, Simone

    2012-03-14

    Colorectal cancer is one of the most common types of cancer in the Western world. Apart from surgery - which remains the mainstay of treatment for resectable primary tumours - postoperative (i.e., adjuvant) chemotherapy with 5-fluorouracil (5-FU) based regimens is now the standard treatment in Dukes' C (TNM stage III) colon tumours i.e. tumours with metastases in the regional lymph nodes but no distant metastases. In contrast, the evidence for recommendations of adjuvant therapy in rectal cancer is sparse. In Europe it is generally acknowledged that locally advanced rectal tumours receive preoperative (i.e., neoadjuvant) downstaging by radiotherapy (or chemoradiotion), whereas in the US postoperative chemoradiotion is considered the treatment of choice in all Dukes' C rectal cancers. Overall, no universal consensus exists on the adjuvant treatment of surgically resectable rectal carcinoma; moreover, no formal systematic review and meta-analysis has been so far performed on this subject. We undertook a systematic review of the scientific literature from 1975 until March 2011 in order to quantitatively summarize the available evidence regarding the impact of postoperative adjuvant chemotherapy on the survival of patients with surgically resectable rectal cancer. The outcomes of interest were overall survival (OS) and disease-free survival (DFS). CCCG standard search strategy in defined databases with the following supplementary search. 1. Rect* or colorect* - 2. Cancer or carcinom* or adenocarc* or neoplasm* or tumour - 3. Adjuv* - 4. Chemother* - 5. Postoper* Randomised controlled trials (RCT) comparing patients undergoing surgery for rectal cancer who received no adjuvant chemotherapy with those receiving any postoperative chemotherapy regimen. Two authors extracted data and a third author performed an independent search for verification. The main outcome measure was the hazard ratio (HR) between the risk of event between the treatment arm (adjuvant chemotherapy

  7. Lipopolysaccharide contamination in intradermal DNA vaccination : toxic impurity or adjuvant?

    NARCIS (Netherlands)

    Berg, J.H. van den; Quaak, S.G.L.; Beijnen, J.H.; Hennink, W.E.; Storm, G.; Schumacher, T.N.; Haanen, J.B.A.G.; Nuijen, B.

    Purpose: Lipopolysaccharides (LPS) are known both as potential adjuvants for vaccines and as toxic impurity in pharmaceutical preparations. The aim of this study was to assess the role of LPS in intradermal DNA vaccination administered by DNA tattooing. Method: Micewere vaccinated with a model DNA

  8. Effects of processing adjuvants on traditional Chinese herbs

    Directory of Open Access Journals (Sweden)

    Lin-Lin Chen

    2018-04-01

    Full Text Available Processing of Chinese medicines is a pharmaceutical technique that transforms medicinal raw materials into decoction pieces for use in different therapies. Various adjuvants, such as vinegar, wine, honey, and brine, are used in the processing to enhance the efficacy and reduce the toxicity of crude drugs. Proper processing is essential to ensure the quality and safety of traditional Chinese medicines (TCMs. Therefore, sound knowledge of processing principles is crucial to the standardized use of these processing adjuvants and to facilitate the production and clinical use of decoction pieces. Many scientific reports have indicated the synergistic effects of processing mechanisms on the chemistry, pharmacology, and pharmacokinetics of the active ingredients in TCMs. Under certain conditions, adjuvants change the content of active or toxic components in drugs by chemical or physical transformation, increase or decrease drug dissolution, exert their own pharmacological effects, or alter drug pharmacokinetics. This review summarizes various processing methods adopted in the last two decades, and highlights current approaches to identify the effects of processing parameters on TCMs. Keywords: Adjuvant, Processing, Synergism, Traditional Chinese medicine

  9. Efficacy of Killed Adjuvanted FMD Vaccine Developed with ...

    African Journals Online (AJOL)

    In this study the potency of killed Foot and Mouth Disease (FMD) vaccines serotypes SAT1 (Nig 1/98) and SAT 2 (Nig 2/97) virus isolates, formulated with montanide ISA 206 adjuvant was determined in guinea pigs and cattle by antibody assay using Complement Fixation and Serum Neutralization tests. The antibody titres ...

  10. A randomised controlled trial comparing the effect of adjuvant ...

    African Journals Online (AJOL)

    Background: Intrathecal adjuvants are added to local anaesthetics to improve the quality of neuraxial blockade and prolong the duration of analgesia during spinal anaesthesia. Used intrathecally, fentanyl improves the quality of spinal blockade as compared to plain bupivacaine and confers a short duration of post ...

  11. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Science.gov (United States)

    2010-04-01

    ... Section 172.710 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The...

  12. Vaccine Adjuvant Incorporation Strategy Dictates Peptide Amphiphile Micelle Immunostimulatory Capacity.

    Science.gov (United States)

    Zhang, Rui; Kramer, Jake S; Smith, Josiah D; Allen, Brittany N; Leeper, Caitlin N; Li, Xiaolei; Morton, Logan D; Gallazzi, Fabio; Ulery, Bret D

    2018-06-01

    Current vaccine research has shifted from traditional vaccines (i.e., whole-killed or live-attenuated) to subunit vaccines (i.e., protein, peptide, or DNA) as the latter is much safer due to delivering only the bioactive components necessary to produce a desirable immune response. Unfortunately, subunit vaccines are very weak immunogens requiring delivery vehicles and the addition of immunostimulatory molecules termed adjuvants to convey protective immunity. An interesting type of delivery vehicle is peptide amphiphile micelles (PAMs), unique biomaterials where the vaccine is part of the nanomaterial itself. Due to the modularity of PAMs, they can be readily modified to deliver both vaccine antigens and adjuvants within a singular construct. Through the co-delivery of a model antigenic epitope (Ovalbumin 319-340 -OVA BT ) and a known molecular adjuvant (e.g., 2,3-dipalmitoyl-S-glyceryl cysteine-Pam 2 C), greater insight into the mechanisms by which PAMs can exert immunostimulatory effects was gained. It was found that specific combinations of antigen and adjuvant can significantly alter vaccine immunogenicity both in vitro and in vivo. These results inform fundamental design rules that can be leveraged to fabricate optimal PAM-based vaccine formulations for future disease-specific applications. Graphical Abstract.

  13. Adjuvant chemotherapy for stage I non-seminomatous testicular ...

    African Journals Online (AJOL)

    Adjuvant chemotherapy for stage I non-seminomatous testicular cancer. R. P. Abratt, A. R. Pontin, R. D. Barnes, B. V. Reddi. Developments in the treatment of stage I ... taxing for patients.·. Analysis of tumour histology in the orchidectomy specimen in patients entered into surveillance studies led to the identification of risk ...

  14. Role of chemoradiotherapy in oesophageal cancer -- adjuvant and neoadjuvant therapy

    NARCIS (Netherlands)

    Gwynne, S.; Wijnhoven, B. P. L.; Hulshof, M.; Bateman, A.

    2014-01-01

    Despite low postoperative mortality rates, the long-term outcomes from surgical-based treatment for oesophageal cancer remain poor. Chemoradiotherapy (CRT), either given before surgical resection as neoadjuvant therapy or after resection as adjuvant therapy, has been postulated to improve these

  15. Influence of Asian dust particles on immune adjuvant effects and airway inflammation in asthma model mice.

    Directory of Open Access Journals (Sweden)

    Jun Kurai

    Full Text Available An Asian dust storm (ADS contains airborne particles that affect conditions such as asthma, but the mechanism of exacerbation is unclear. The objective of this study was to compare immune adjuvant effects and airway inflammation induced by airborne particles collected on ADS days and the original ADS soil (CJ-1 soil in asthma model mice.Airborne particles were collected on ADS days in western Japan. NC/Nga mice were co-sensitized by intranasal instillation with ADS airborne particles and/or Dermatophagoides farinae (Df, and with CJ-1 soil and/or Df for 5 consecutive days. Df-sensitized mice were stimulated with Df challenge intranasally at 7 days after the last Df sensitization. At 24 hours after challenge, serum allergen specific antibody, differential leukocyte count and inflammatory cytokines in bronchoalveolar lavage fluid (BALF were measured, and airway inflammation was examined histopathologically.Co-sensitization with ADS airborne particles and Df increased the neutrophil and eosinophil counts in BALF. Augmentation of airway inflammation was also observed in peribronchiolar and perivascular lung areas. Df-specific serum IgE was significantly elevated by ADS airborne particles, but not by CJ-1 soil. Levels of interleukin (IL-5, IL-13, IL-6, and macrophage inflammatory protein-2 were higher in BALF in mice treated with ADS airborne particles.These results suggest that substances attached to ADS airborne particles that are not in the original ADS soil may play important roles in immune adjuvant effects and airway inflammation.

  16. Retinaldehyde dehydrogenase 2 as a molecular adjuvant for enhancement of mucosal immunity during DNA vaccination.

    Science.gov (United States)

    Holechek, Susan A; McAfee, Megan S; Nieves, Lizbeth M; Guzman, Vanessa P; Manhas, Kavita; Fouts, Timothy; Bagley, Kenneth; Blattman, Joseph N

    2016-11-04

    In order for vaccines to induce efficacious immune responses against mucosally transmitted pathogens, such as HIV-1, activated lymphocytes must efficiently migrate to and enter targeted mucosal sites. We have previously shown that all-trans retinoic acid (ATRA) can be used as a vaccine adjuvant to enhance mucosal CD8 + T cell responses during vaccination and improve protection against mucosal viral challenge. However, the ATRA formulation is incompatible with most recombinant vaccines, and the teratogenic potential of ATRA at high doses limits its usage in many clinical settings. We hypothesized that increasing in vivo production of retinoic acid (RA) during vaccination with a DNA vector expressing retinaldehyde dehydrogenase 2 (RALDH2), the rate-limiting enzyme in RA biosynthesis, could similarly provide enhanced programming of mucosal homing to T cell responses while avoiding teratogenic effects. Administration of a RALDH2- expressing plasmid during immunization with a HIVgag DNA vaccine resulted in increased systemic and mucosal CD8 + T cell numbers with an increase in both effector and central memory T cells. Moreover, mice that received RALDH2 plasmid during DNA vaccination were more resistant to intravaginal challenge with a recombinant vaccinia virus expressing the same HIVgag antigen (VACVgag). Thus, RALDH2 can be used as an alternative adjuvant to ATRA during DNA vaccination leading to an increase in both systemic and mucosal T cell immunity and better protection from viral infection at mucosal sites. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. A Protective Vaccine against Chlamydia Genital Infection Using Vault Nanoparticles without an Added Adjuvant.

    Science.gov (United States)

    Jiang, Janina; Liu, Guangchao; Kickhoefer, Valerie A; Rome, Leonard H; Li, Lin-Xi; McSorley, Stephen J; Kelly, Kathleen A

    2017-01-19

    Chlamydia trachomatis genital infection is the most common sexually transmitted bacterial disease, causing a significant burden to females due to reproductive dysfunction. Intensive screening and antibiotic treatment are unable to completely prevent female reproductive dysfunction, thus, efforts have become focused on developing a vaccine. A major impediment is identifying a safe and effective adjuvant which induces cluster of differentiation 4 (CD4) cells with attributes capable of halting genital infection and inflammation. Previously, we described a natural nanocapsule called the vault which was engineered to contain major outer membrane protein (MOMP) and was an effective vaccine which significantly reduced early infection and favored development of a cellular immune response in a mouse model. In the current study, we used another chlamydial antigen, a polymorphic membrane protein G-1 (PmpG) peptide, to track antigen-specific cells and evaluate, in depth, the vault vaccine for its protective capacity in the absence of an added adjuvant. We found PmpG-vault immunized mice significantly reduced the genital bacterial burden and histopathologic parameters of inflammation following a C. muridarum challenge. Immunization boosted antigen-specific CD4 cells with a multiple cytokine secretion pattern and reduced the number of inflammatory cells in the genital tract making the vault vaccine platform safe and effective for chlamydial genital infection. We conclude that vaccination with a Chlamydia -vault vaccine boosts antigen-specific immunities that are effective at eradicating infection and preventing reproductive tract inflammation.

  18. A Protective Vaccine against Chlamydia Genital Infection Using Vault Nanoparticles without an Added Adjuvant

    Directory of Open Access Journals (Sweden)

    Janina Jiang

    2017-01-01

    Full Text Available Chlamydia trachomatis genital infection is the most common sexually transmitted bacterial disease, causing a significant burden to females due to reproductive dysfunction. Intensive screening and antibiotic treatment are unable to completely prevent female reproductive dysfunction, thus, efforts have become focused on developing a vaccine. A major impediment is identifying a safe and effective adjuvant which induces cluster of differentiation 4 (CD4 cells with attributes capable of halting genital infection and inflammation. Previously, we described a natural nanocapsule called the vault which was engineered to contain major outer membrane protein (MOMP and was an effective vaccine which significantly reduced early infection and favored development of a cellular immune response in a mouse model. In the current study, we used another chlamydial antigen, a polymorphic membrane protein G-1 (PmpG peptide, to track antigen-specific cells and evaluate, in depth, the vault vaccine for its protective capacity in the absence of an added adjuvant. We found PmpG-vault immunized mice significantly reduced the genital bacterial burden and histopathologic parameters of inflammation following a C. muridarum challenge. Immunization boosted antigen-specific CD4 cells with a multiple cytokine secretion pattern and reduced the number of inflammatory cells in the genital tract making the vault vaccine platform safe and effective for chlamydial genital infection. We conclude that vaccination with a Chlamydia-vault vaccine boosts antigen-specific immunities that are effective at eradicating infection and preventing reproductive tract inflammation.

  19. A network-based predictive gene-expression signature for adjuvant chemotherapy benefit in stage II colorectal cancer.

    Science.gov (United States)

    Cao, Bangrong; Luo, Liping; Feng, Lin; Ma, Shiqi; Chen, Tingqing; Ren, Yuan; Zha, Xiao; Cheng, Shujun; Zhang, Kaitai; Chen, Changmin

    2017-12-13

    The clinical benefit of adjuvant chemotherapy for stage II colorectal cancer (CRC) is controversial. This study aimed to explore novel gene signature to predict outcome benefit of postoperative 5-Fu-based therapy in stage II CRC. Gene-expression profiles of stage II CRCs from two datasets with 5-Fu-based adjuvant chemotherapy (training dataset, n = 212; validation dataset, n = 85) were analyzed to identify the indicator. A systemic approach by integrating gene-expression and protein-protein interaction (PPI) network was implemented to develop the predictive signature. Kaplan-Meier curves and Cox proportional hazards model were used to determine the survival benefit of adjuvant chemotherapy. Experiments with shRNA knock-down were carried out to confirm the signature identified in this study. In the training dataset, we identified 44 PPI sub-modules, by which we separate patients into two clusters (1 and 2) having different chemotherapeutic benefit. A predictor of 11 PPI sub-modules (11-PPI-Mod) was established to discriminate the two sub-groups, with an overall accuracy of 90.1%. This signature was independently validated in an external validation dataset. Kaplan-Meier curves showed an improved outcome for patients who received adjuvant chemotherapy in Cluster 1 sub-group, but even worse survival for those in Cluster 2 sub-group. Similar results were found in both the training and the validation dataset. Multivariate Cox regression revealed an interaction effect between 11-PPI-Mod signature and adjuvant therapy treatment in the training dataset (RFS, p = 0.007; OS, p = 0.006) and the validation dataset (RFS, p = 0.002). From the signature, we found that PTGES gene was up-regulated in CRC cells which were more resistant to 5-Fu. Knock-down of PTGES indicated a growth inhibition and up-regulation of apoptotic markers induced by 5-Fu in CRC cells. Only a small proportion of stage II CRC patients could benefit from adjuvant therapy. The 11-PPI-Mod as

  20. Poly(I:C) adjuvant strongly enhances parasite-inhibitory antibodies and Th1 response against Plasmodium falciparum merozoite surface protein-1 (42-kDa fragment) in BALB/c mice.

    Science.gov (United States)

    Mehrizi, Akram Abouie; Rezvani, Niloufar; Zakeri, Sedigheh; Gholami, Atefeh; Babaeekhou, Laleh

    2018-04-01

    Malaria vaccine development has been confronted with various challenges such as poor immunogenicity of malaria vaccine candidate antigens, which is considered as the main challenge. However, this problem can be managed using appropriate formulations of antigens and adjuvants. Poly(I:C) is a potent Th1 inducer and a human compatible adjuvant capable of stimulating both B- and T-cell immunity. Plasmodium falciparum merozoite surface protein 1 42 (PfMSP-1 42 ) is a promising vaccine candidate for blood stage of malaria that has faced several difficulties in clinical trials, mainly due to improper adjuvants. Therefore, in the current study, poly(I:C), as a potent Th1 inducer adjuvant, was evaluated to improve the immunogenicity of recombinant PfMSP-1 42 , when compared to CFA/IFA, as reference adjuvant. Poly(I:C) produced high level and titers of anti-PfMSP-1 42 IgG antibodies in which was comparable to CFA/IFA adjuvant. In addition, PfMSP-1 42 formulated with poly(I:C) elicited a higher ratio of IFN-γ/IL-4 (23.9) and IgG2a/IgG1 (3.77) with more persistent, higher avidity, and titer of IgG2a relative to CFA/IFA, indicating a potent Th1 immune response. Poly(I:C) could also help to induce anti-PfMSP-1 42 antibodies with higher growth-inhibitory activity than CFA/IFA. Altogether, the results of the current study demonstrated that poly(I:C) is a potent adjuvant that can be appropriate for being used in PfMSP-1 42 -based vaccine formulations.

  1. Comparative Safety and Efficacy Profile of a Novel Oil in Water Vaccine Adjuvant Comprising Vitamins A and E and a Catechin in Protective Anti-Influenza Immunity

    Directory of Open Access Journals (Sweden)

    Sapna Patel

    2017-05-01

    Full Text Available Non-replicating vaccines, such as those based on recombinant proteins, require adjuvants and delivery systems, which have thus far depended on mimicking pathogen danger signals and strong pro-inflammatory responses. In search of a safer and more efficacious alternative, we tested whether vaccinations with influenza recombinant hemagglutinin (HA mixed with a novel vegetable oil in water emulsion adjuvant (Natural Immune-enhancing Delivery System, NIDS, based on the immune-enhancing synergy of vitamins A and E and a catechin, could protect against intra-nasal challenge with live influenza virus. Vaccinations of inbred Brag Albino strain c (BALB/c mice, with HA mixed with NIDS compared to other adjuvants, i.e., a squalene oil in water emulsion (Sq. oil, and the Toll Like Receptor 3 (TLR3 agonist Poly (I:C, induced significantly lower select innate pro-inflammatory responses in serum, but induced significantly higher adaptive antibody and splenic T Helper 1 (TH1 or TH2, but not TH17, responses. Vaccinations with NIDS protected against infection, as measured by clinical scores, lung viral loads, and serum hemagglutination inhibition titers. The NIDS exhibited a strong dose sparing effect and the adjuvant action of NIDS was intact in the outbred CD1 mice. Importantly, vaccinations with the Sq. oil, but not NIDS, induced a significantly higher Serum Amyloid P component, an acute phase reactant secreted by hepatocytes, and total serum IgE. Thus, the NIDS may be used as a clinically safer and more efficacious vaccine adjuvant against influenza, and potentially other infectious diseases.

  2. Delta inulin-derived adjuvants that elicit Th1 phenotype following vaccination reduces respiratory syncytial virus lung titers without a reduction in lung immunopathology.

    Science.gov (United States)

    Wong, Terianne M; Petrovsky, Nikolai; Bissel, Stephanie J; Wiley, Clayton A; Ross, Ted M

    2016-08-02

    Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract infections resulting in bronchiolitis and even mortality in the elderly and young children/infants. Despite the impact of this virus on human health, no licensed vaccine exists. Unlike many other viral infections, RSV infection or vaccination does not induce durable protective antibodies in humans. In order to elicit high titer, neutralizing antibodies against RSV, we investigated the use of the adjuvant Advax™, a novel polysaccharide adjuvant based on delta inulin microparticles, to enhance antibody titers following vaccination. BALB/c mice were vaccinated intramuscularly with live RSV as a vaccine antigen in combination with one of two formulations of Advax™. Advax-1 was comprised of the standard delta inulin adjuvant and Advax-2 was formulated delta inulin plus CpG oligodendronucleotides (ODNs). An additional group of mice were either mock vaccinated, immunized with vaccine only, or administered vaccine plus Imject Alum. Following 3 vaccinations, mice had neutralizing antibody titers that correlated with reduction in viral titers in the lungs. Advax-1 significantly enhanced serum RSV-specific IgG1 levels at week 6 indicative of a Th2 response, similar to titers in mice administered vaccine plus Imject Alum. In contrast, mice vaccinated with vaccine plus Advax-2 had predominately IgG2a titers indicative of a Th1 response that was maintained during the entire study. Interestingly, regardless of which Advax TM adjuvant was used, the neutralizing titers were similar between groups, but the viral lung titers were significantly lower (∼10E+3pfu/g) in mice administered vaccine with either Advax TM adjuvant compared to mice administered adjuvants only. The lung pathology in vaccinated mice with Advax TM was similar to Imject Alum. Overall, RSV vaccine formulated with Advax TM had high neutralizing antibody titers with low lung viral titers, but exacerbated lung pathology compared

  3. Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice.

    Science.gov (United States)

    Paes, Wayne; Brown, Naj; Brzozowski, Andrzej M; Coler, Rhea; Reed, Steve; Carter, Darrick; Bland, Martin; Kaye, Paul M; Lacey, Charles J N

    2016-07-29

    The development of a chlamydial vaccine that elicits protective mucosal immunity is of paramount importance in combatting the global spread of sexually transmitted Chlamydia trachomatis (Ct) infections. While the identification and prioritization of chlamydial antigens is a crucial prerequisite for efficacious vaccine design, it is likely that novel adjuvant development and selection will also play a pivotal role in the translational potential of preclinical Ct vaccines. Although the molecular nature of the immuno-modulatory component is of primary importance, adjuvant formulation and delivery systems may also govern vaccine efficacy and potency. Our study provides the first preclinical evaluation of recombinant Ct polymorphic membrane protein D (rPmpD) in combination with three different formulations of a novel second-generation lipid adjuvant (SLA). SLA was rationally designed in silico by modification of glucopyranosyl lipid adjuvant (GLA), a TLR4 agonistic precursor molecule currently in Phase II clinical development. We demonstrate robust protection against intra-vaginal Ct challenge in mice, evidenced by significantly enhanced resistance to infection and reduction in mean bacterial load. Strikingly, protection was found to correlate with the presence of robust anti-rPmpD serum and cervico-vaginal IgG titres, even in the absence of adjuvant-induced Th1-type cellular immune responses elicited by each SLA formulation, and we further show that anti-rPmpD antibodies recognize Ct EBs. These findings highlight the utility of SLA and rational molecular design of adjuvants in preclinical Ct vaccine development, but also suggest an important role for anti-rPmpD antibodies in protection against urogenital Ct infection. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  4. A CpG-containing oligodeoxynucleotide as an efficient adjuvant counterbalancing the Th1/Th2 immune response in diphtheria-tetanus-pertussis vaccine.

    Science.gov (United States)

    Sugai, Toshiyuki; Mori, Masaaki; Nakazawa, Masatoshi; Ichino, Motohide; Naruto, Takuya; Kobayashi, Naoki; Kobayashi, Yoshinori; Minami, Mutsuhiko; Yokota, Shumpei

    2005-11-16

    Adjuvants in vaccines are immune stimulants that play an important role in the induction of effective and appropriate immune responses to vaccine component(s). Diphtheria-tetanus-pertussis (DPT) vaccine contains not only aluminum hydrate (alum) to enhance the immune response to the vaccine ingredients, but also, both for that purpose and as a principal ingredient, pertussis toxin (PT). However, both adjuvants strongly promote T helper (Th) 2 type immune responses. Th1 and Th2 type immune responses are counterbalanced in vivo, and a Th2-prone immune response is not effective against intracellular infections but promotes IgE production, which is related to allergic disease. In this study, we used the CpG motif contained in oligodeoxynucleotide (CpG-ODN), which has an adjuvant effect and also induces the Th1 response, as an adjuvant to this vaccine, and we investigated its adjuvanticity and its potential to modulate immune responses to DPT vaccine. Administration of DPT vaccine with CpG-ODN (DPT-alum/ODN) to mice significantly reduced the total IgE levels and increased the anti-PT specific IgG2a titer in serum, in comparison with ordinary DPT vaccine (DPT-alum). Moreover, we investigated the antibody response to orally administrated ovalbumin (OVA) after vaccine administration. In the DPT-alum/ODN-administered group, the OVA specific IgE production in serum greatly decreased in comparison with that in the DPT-alum-administered group. These data indicate that CpG-ODN was not useful only as an efficient vaccine adjuvant but also shifted the immune responses substantially toward Th1 and modulated the Th1/Th2 immune response in DPT vaccine. These data suggested new applications of CpG-ODN as adjuvants in DPT vaccine.

  5. Investigations of immunogenic, allergenic and adjuvant properties of Cry1Ab protein after intragastric exposure in a food allergy model in mice.

    Science.gov (United States)

    Andreassen, Monica; Bøhn, Thomas; Wikmark, Odd-Gunnar; Bodin, Johanna; Traavik, Terje; Løvik, Martinus; Nygaard, Unni Cecilie

    2016-05-04

    In genetically modified (GM) crops there is a risk that the inserted genes may introduce new allergens and/or adjuvants into the food and feed chain. The MON810 maize, expressing the insecticidal Cry1Ab toxin, is grown in many countries worldwide. In animal models, intranasal and intraperitoneal immunisations with the purified Cry1Ab proteins have induced immune responses, and feeding trials with Cry1Ab-containing feed have revealed some altered immune responses. Previous investigations have primarily measured antibody responses to the protein, while investigations of clinical food allergy symptoms, or allergy promotion (adjuvant effect) associated with the Cry1Ab protein are largely missing. We aimed to investigate immunogenic, allergenic and adjuvant properties of purified Cry1Ab toxin (trypCry1Ab, i.e., trypsin activated Cry1Ab) in a mouse model of food allergy. Female C3H/HeJ mice were immunized by intragastric gavage of 10 μg purified, trypsin activated Cry1Ab toxin (trypCry1Ab) alone or together with the food allergen lupin. Cholera toxin was added as a positive control for adjuvant effect to break oral tolerance. Clinical symptoms (anaphylaxis) as well as humoral and cellular responses were assessed. In contrast to results from previous airway investigations, we observed no indication of immunogenic properties of trypCry1Ab protein after repeated intragastric exposures to one dose, with or without CT as adjuvant. Moreover, the results indicated that trypCry1Ab given by the intragastric route was not able to promote allergic responses or anaphylactic reactions against the co-administered allergen lupin at the given dose. The study suggests no immunogenic, allergenic or adjuvant capacity of the given dose of trypCry1Ab protein after intragastric exposure of prime aged mice.

  6. Air Pollution and Climate Change Effects on Allergies in the Anthropocene: Abundance, Interaction, and Modification of Allergens and Adjuvants.

    Science.gov (United States)

    Reinmuth-Selzle, Kathrin; Kampf, Christopher J; Lucas, Kurt; Lang-Yona, Naama; Fröhlich-Nowoisky, Janine; Shiraiwa, Manabu; Lakey, Pascale S J; Lai, Senchao; Liu, Fobang; Kunert, Anna T; Ziegler, Kira; Shen, Fangxia; Sgarbanti, Rossella; Weber, Bettina; Bellinghausen, Iris; Saloga, Joachim; Weller, Michael G; Duschl, Albert; Schuppan, Detlef; Pöschl, Ulrich

    2017-04-18

    Air pollution and climate change are potential drivers for the increasing burden of allergic diseases. The molecular mechanisms by which air pollutants and climate parameters may influence allergic diseases, however, are complex and elusive. This article provides an overview of physical, chemical and biological interactions between air pollution, climate change, allergens, adjuvants and the immune system, addressing how these interactions may promote the development of allergies. We reviewed and synthesized key findings from atmospheric, climate, and biomedical research. The current state of knowledge, open questions, and future research perspectives are outlined and discussed. The Anthropocene, as the present era of globally pervasive anthropogenic influence on planet Earth and, thus, on the human environment, is characterized by a strong increase of carbon dioxide, ozone, nitrogen oxides, and combustion- or traffic-related particulate matter in the atmosphere. These environmental factors can enhance the abundance and induce chemical modifications of allergens, increase oxidative stress in the human body, and skew the immune system toward allergic reactions. In particular, air pollutants can act as adjuvants and alter the immunogenicity of allergenic proteins, while climate change affects the atmospheric abundance and human exposure to bioaerosols and aeroallergens. To fully understand and effectively mitigate the adverse effects of air pollution and climate change on allergic diseases, several challenges remain to be resolved. Among these are the identification and quantification of immunochemical reaction pathways involving allergens and adjuvants under relevant environmental and physiological conditions.

  7. The Immunomodulatory Role of Adjuvants in Vaccines Formulated with the Recombinant Antigens Ov-103 and Ov-RAL-2 against Onchocerca volvulus in Mice.

    Directory of Open Access Journals (Sweden)

    Jessica A Hess

    2016-07-01

    Full Text Available In some regions in Africa, elimination of onchocerciasis may be possible with mass drug administration, although there is concern based on several factors that onchocerciasis cannot be eliminated solely through this approach. A vaccine against Onchocerca volvulus would provide a critical tool for the ultimate elimination of this infection. Previous studies have demonstrated that immunization of mice with Ov-103 and Ov-RAL-2, when formulated with alum, induced protective immunity. It was hypothesized that the levels of protective immunity induced with the two recombinant antigens formulated with alum would be improved by formulation with other adjuvants known to enhance different types of antigen-specific immune responses.Immunizing mice with Ov-103 and Ov-RAL-2 in conjunction with alum, Advax 2 and MF59 induced significant levels of larval killing and host protection. The immune response was biased towards Th2 with all three of the adjuvants, with IgG1 the dominant antibody. Improved larval killing and host protection was observed in mice immunized with co-administered Ov-103 and Ov-RAL-2 in conjunction with each of the three adjuvants as compared to single immunizations. Antigen-specific antibody titers were significantly increased in mice immunized concurrently with the two antigens. Based on chemokine levels, it appears that neutrophils and eosinophils participate in the protective immune response induced by Ov-103, and macrophages and neutrophils participate in immunity induced by Ov-RAL-2.The mechanism of protective immunity induced by Ov-103 and Ov-RAL-2, with the adjuvants alum, Advax 2 and MF59, appears to be multifactorial with roles for cytokines, chemokines, antibody and specific effector cells. The vaccines developed in this study have the potential of reducing the morbidity associated with onchocerciasis in humans.

  8. [Status and suggestions for adjuvant standard for Chinese materia medica processing in China].

    Science.gov (United States)

    Yang, Chun-Yu; Cao, Hui; Wang, Xiao-Tao; Tu, Jia-Sheng; Qian, Zhong-Zhi; Yu, Zhi-Ling; Shang, Yue; Zhang, Bao-Xian

    2017-04-01

    In this paper, the status of adjuvant standard for Chinese materia medica processing in the Chinese Pharmacopoeia 2015 edition, the National Specification of Chinese Materia Medica Processing, and the 29 provincial specification of Chinese materia medica was summarized, and the the status including general requirements, specific requirements, and quality standard in the three grade official specifications was collected and analyzed according to the "medicine-adjuvant homology" and "food-adjuvant homology" features of adjuvants. This paper also introduced the research situation of adjuvant standard for Chinese materia medica processing in China; In addition, analyzed and discussed the problems existing in the standard system of adjuvant for Chinese materia medica processing, such as lack of general requirements, low level of standard, inconsistent standard references, and lack of research on the standard, and provided suggestions for the further establishment of the national standards system of adjuvant for Chinese materia medica processing. Copyright© by the Chinese Pharmaceutical Association.

  9. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer – the RAPIDO trial

    International Nuclear Information System (INIS)

    Nilsson, Per J; Marijnen, Corrie AM; Nagtegaal, Iris D; Wiggers, Theo; Glimelius, Bengt; Etten, Boudewijn van; Hospers, Geke AP; Påhlman, Lars; Velde, Cornelis JH van de; Beets-Tan, Regina GH; Blomqvist, Lennart; Beukema, Jannet C; Kapiteijn, Ellen

    2013-01-01

    Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer. Patients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life. Following the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative

  10. A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children.

    Science.gov (United States)

    Stassijns, Jorgen; Bollaerts, Kaatje; Baay, Marc; Verstraeten, Thomas

    2016-02-03

    New adjuvants such as the AS- or the MF59-adjuvants improve vaccine efficacy and facilitate dose-sparing. Their use in influenza and malaria vaccines has resulted in a large body of evidence on their clinical safety in children. We carried out a systematic search for safety data from published clinical trials on newly adjuvanted vaccines in children ≤10 years of age. Serious adverse events (SAEs), solicited AEs, unsolicited AEs and AEs of special interest were evaluated for four new adjuvants: the immuno-stimulants containing adjuvant systems AS01 and AS02, and the squalene containing oil-in-water emulsions AS03 and MF59. Relative risks (RR) were calculated, comparing children receiving newly adjuvanted vaccines to children receiving other vaccines with a variety of antigens, both adjuvanted and unadjuvanted. Twenty-nine trials were included in the meta-analysis, encompassing 25,056 children who received at least one dose of the newly adjuvanted vaccines. SAEs did not occur more frequently in adjuvanted groups (RR 0.85, 95%CI 0.75-0.96). Our meta-analyses showed higher reactogenicity following administration of newly adjuvanted vaccines, however, no consistent pattern of solicited AEs was observed across adjuvant systems. Pain was the most prevalent AE, but often mild and of short duration. No increased risks were found for unsolicited AEs, febrile convulsions, potential immune mediated diseases and new onset of chronic diseases. Our meta-analysis did not show any safety concerns in clinical trials of the newly adjuvanted vaccines in children ≤10 years of age. An unexplained increase of meningitis in one Phase III AS01-adjuvanted malaria trial and the link between narcolepsy and the AS03-adjuvanted pandemic vaccine illustrate that continued safety monitoring is warranted. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Immunoendocrine Interactions during HIV-TB Coinfection: Implications for the Design of New Adjuvant Therapies

    Directory of Open Access Journals (Sweden)

    Guadalupe Veronica Suarez

    2015-01-01

    Full Text Available Worldwide, around 14 million individuals are coinfected with both tuberculosis (TB and human immunodeficiency virus (HIV. In coinfected individuals, both pathogens weaken immunological system synergistically through mechanisms that are not fully understood. During both HIV and TB infections, there is a chronic state of inflammation associated to dramatic changes in immune cytokine and endocrine hormone levels. Despite this, the relevance of immunoendocrine interaction on both the orchestration of an effective immune response against both pathogens and the control of the chronic inflammation induced during HIV, TB, or both infections is still controversial. The present study reviews immunoendocrine interactions occurring during HIV and TB infections. We also expose our own findings on immunoendocrine cross talk in HIV-TB coinfection. Finally, we evaluate the use of adrenal hormones and their derivatives in immune-therapy and discuss the use of some of these compounds like the adjuvant for the prevention and treatment of TB in HIV patients.

  12. Chronic Pain and Neuropathy Following Adjuvant Chemotherapy

    DEFF Research Database (Denmark)

    Ventzel, Lise; Madsen, Caspar S; Karlsson, Páll

    2017-01-01

    Objective: To determine symptoms and characteristics of chronic sensory neuropathy in patients treated with oxaliplatin and docetaxel, including patterns of somatosensory abnormalities, pain descriptors, and psychological functioning. Design: A retrospective cross-sectional study. Setting: A chro...... mechanisms useful for future studies in the tailored treatment of prevention of chemotherapy-induced peripheral neuropathy and pain.......Objective: To determine symptoms and characteristics of chronic sensory neuropathy in patients treated with oxaliplatin and docetaxel, including patterns of somatosensory abnormalities, pain descriptors, and psychological functioning. Design: A retrospective cross-sectional study. Setting......: A chronic pain research center. Subjects: Thirty-eight patients with chronic peripheral pain and/or dysesthesia following chemotherapy. Methods:  Sensory profiles, psychological functioning, and quality of life were assessed using standardized questionnaires. In addition, standardized quantitative sensory...

  13. [Different aluminum adjuvants significantly enhances the effect of immunization on Brucella Omp31].

    Science.gov (United States)

    Qing, Rui; Xiang, Qingke; Liu, Zhongqi; Xiao, Fei; Yang, Fan

    2018-02-01

    Objective To investigate the effect of aluminum phosphate (AP) and aluminum hydroxide (AH) as adjuvants on Brucella outer membrane protein 31 (Omp31) in inducing humoral and cellular immune responses and immune protection. Methods AP and AH adjuvants were prepared and separately mixed with Brucella Omp31 protein to measure the adsorption rates. The AP- and AH-absorbed Omp31 protein were intraperitoneally injected into BLAB/c mice at 0, 2, and 4 weeks, and meanwhile, unabsorbed Omp31 protein and PBS were used as controls. The levels of serum IgG, IgG1, IgG2a and genital tract secretion sIgA were determined by ELISA at 0, 2, 4 and 6 weeks. Spleen cells were collected for culture at 6 weeks, and the cells were stimulated by Omp31 for 48 hours followed by the analysis of IFN-γ and IL-10 levels in the supernatants by ELISA, and the determination of lymphocyte proliferation by CCK-8 assay. The mice were challenged with Brucella at 6 weeks, and bacterial content in spleen tissue was determined 1 and 2 weeks later. Results AP and AH could absorb over 70% and 85% of the Omp31 protein, respectively, for solutions at all the tested concentrations. ELISA suggested that serum IgG, IgG1, IgG2a and genital tract sIgA levels peaked 2 weeks after the last immunization for both AP and AH groups, and antibody level was higher in the AP and AH groups than the control groups, and higher in the AH group than in the AP group. CCK-8 assay showed that the proliferating rate of lymphocytes induced by the AH group was significantly higher than that by the AP group, and the AH group also showed significantly higher IFN-γ level in the supernatant than the AP group, but no significant difference in IL-10 level. The AH group had remarkably lower bacterial load in the spleen than the AP group 2 weeks after challenged by Brucella 16M strain. Conclusion Both AP and AH adjuvants effectively enhanced immunogenicity and immune protection of the Brucella Omp31 protein, and AH was superior to AP in

  14. The mucosal adjuvant cholera toxin B instructs non-mucosal dendritic cells to promote IgA production via retinoic acid and TGF-β.

    Directory of Open Access Journals (Sweden)

    Anouk K Gloudemans

    Full Text Available It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA, and how T cell-dependent (TD or -independent (TI pathways might be involved. Mucosal dendritic cells (DCs are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL, B cell activating factor (BAFF, Retinoic Acid (RA, TGF-β or nitric oxide (NO. We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-β signaling inhibitor or neutralizing anti-TGF-β was added, demonstrating the involvement of RA and TGF-β in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant.

  15. The mucosal adjuvant cholera toxin B instructs non-mucosal dendritic cells to promote IgA production via retinoic acid and TGF-β.

    Science.gov (United States)

    Gloudemans, Anouk K; Plantinga, Maud; Guilliams, Martin; Willart, Monique A; Ozir-Fazalalikhan, Arifa; van der Ham, Alwin; Boon, Louis; Harris, Nicola L; Hammad, Hamida; Hoogsteden, Henk C; Yazdanbakhsh, Maria; Hendriks, Rudi W; Lambrecht, Bart N; Smits, Hermelijn H

    2013-01-01

    It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA), and how T cell-dependent (TD) or -independent (TI) pathways might be involved. Mucosal dendritic cells (DCs) are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL), B cell activating factor (BAFF), Retinoic Acid (RA), TGF-β or nitric oxide (NO). We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB) could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR) ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-β signaling inhibitor or neutralizing anti-TGF-β was added, demonstrating the involvement of RA and TGF-β in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant.

  16. AFCo1, a meningococcal B-derived cochleate adjuvant, strongly enhances antibody and T-cell immunity against Plasmodium falciparum merozoite surface protein 4 and 5.

    Science.gov (United States)

    Bracho, Gustavo; Zayas, Caridad; Wang, Lina; Coppel, Ross; Pérez, Oliver; Petrovsky, Nikolai

    2009-02-27

    Whilst a large number of malaria antigens are being tested as candidate malaria vaccines, a major barrier to the development of an effective vaccine is the lack of a suitable human adjuvant capable of inducing a strong and long lasting immune response. In this study, the ability of AFCo1, a potent T and B cell adjuvant based on cochleate structures derived from meningococcal B outer membrane proteoliposomes (MBOMP), to boost the immune response against two Plasmodium falciparum antigens, merozoite surface protein 4 (MSP4) and 5 (MSP5), was evaluated. Complete Freund's adjuvant (CFA), which is able to confer protection against malaria in animal MSP4/5 vaccine challenge models, was used as positive control adjuvant. MSP4 and 5-specific IgG, delayed-type hypersensitivity (DTH), T-cell proliferation, and cytokine production were evaluated in parallel in mice immunized three times intramuscularly with MSP4 or MSP5 incorporated into AFCo1, synthetic cochleate structures, CFA or phosphate buffered saline. AFCo1 significantly enhanced the IgG and T-cell response against MSP4 and MSP5, with a potency equivalent to CFA, with the response being characterized by both IgG1 and IgG2a isotypes, increased interferon gamma production and a strong DTH response, consistent with the ability of AFCo1 to induce Th1-like immune responses. Given the proven safety of MBOMP, which is already in use in a licensed human vaccine, AFCo1 could assist the development of human malaria vaccines that require a potent and safe adjuvant.

  17. AFCo1, a meningococcal B-derived cochleate adjuvant, strongly enhances antibody and T-cell immunity against Plasmodium falciparum merozoite surface protein 4 and 5

    Directory of Open Access Journals (Sweden)

    Pérez Oliver

    2009-02-01

    Full Text Available Abstract Background Whilst a large number of malaria antigens are being tested as candidate malaria vaccines, a major barrier to the development of an effective vaccine is the lack of a suitable human adjuvant capable of inducing a strong and long lasting immune response. In this study, the ability of AFCo1, a potent T and B cell adjuvant based on cochleate structures derived from meningococcal B outer membrane proteoliposomes (MBOMP, to boost the immune response against two Plasmodium falciparum antigens, merozoite surface protein 4 (MSP4 and 5 (MSP5, was evaluated. Methods Complete Freund's adjuvant (CFA, which is able to confer protection against malaria in animal MSP4/5 vaccine challenge models, was used as positive control adjuvant. MSP4 and 5-specific IgG, delayed-type hypersensitivity (DTH, T-cell proliferation, and cytokine production were evaluated in parallel in mice immunized three times intramuscularly with MSP4 or MSP5 incorporated into AFCo1, synthetic cochleate structures, CFA or phosphate buffered saline. Results AFCo1 significantly enhanced the IgG and T-cell response against MSP4 and MSP5, with a potency equivalent to CFA, with the response being characterized by both IgG1 and IgG2a isotypes, increased interferon gamma production and a strong DTH response, consistent with the ability of AFCo1 to induce Th1-like immune responses. Conclusion Given the proven safety of MBOMP, which is already in use in a licensed human vaccine, AFCo1 could assist the development of human malaria vaccines that require a potent and safe adjuvant.

  18. Cerebral biochemical pathways in experimental autoimmune encephalomyelitis and adjuvant arthritis: a comparative metabolomic study.

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    Norbert W Lutz

    Full Text Available Many diseases, including brain disorders, are associated with perturbations of tissue metabolism. However, an often overlooked issue is the impact that inflammations outside the brain may have on brain metabolism. Our main goal was to study similarities and differences between brain metabolite profiles of animals suffering from experimental autoimmune encephalomyelitis (EAE and adjuvant arthritis (AA in Lewis rat models. Our principal objective was the determination of molecular protagonists involved in the metabolism underlying these diseases. EAE was induced by intraplantar injection of complete Freund's adjuvant (CFA and spinal-cord homogenate (SC-H, whereas AA was induced by CFA only. Naive rats served as controls (n = 9 for each group. Two weeks after inoculation, animals were sacrificed, and brains were removed and processed for metabolomic analysis by NMR spectroscopy or for immunohistochemistry. Interestingly, both inflammatory diseases caused similar, though not identical, changes in metabolites involved in regulation of brain cell size and membrane production: among the osmolytes, taurine and the neuronal marker, N-acetylaspartate, were decreased, and the astrocyte marker, myo-inositol, slightly increased in both inoculated groups compared with controls. Also ethanolamine-containing phospholipids, sources of inflammatory agents, and several glycolytic metabolites were increased in both inoculated groups. By contrast, the amino acids, aspartate and isoleucine, were less concentrated in CFA/SC-H and control vs. CFA rats. Our results suggest that inflammatory brain metabolite profiles may indicate the existence of either cerebral (EAE or extra-cerebral (AA inflammation. These inflammatory processes may act through distinct pathways that converge toward similar brain metabolic profiles. Our findings open new avenues for future studies aimed at demonstrating whether brain metabolic effects provoked by AA are pain/stress-mediated and

  19. Cerebral biochemical pathways in experimental autoimmune encephalomyelitis and adjuvant arthritis: a comparative metabolomic study.

    Science.gov (United States)

    Lutz, Norbert W; Fernandez, Carla; Pellissier, Jean-François; Cozzone, Patrick J; Béraud, Evelyne

    2013-01-01

    Many diseases, including brain disorders, are associated with perturbations of tissue metabolism. However, an often overlooked issue is the impact that inflammations outside the brain may have on brain metabolism. Our main goal was to study similarities and differences between brain metabolite profiles of animals suffering from experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rat models. Our principal objective was the determination of molecular protagonists involved in the metabolism underlying these diseases. EAE was induced by intraplantar injection of complete Freund's adjuvant (CFA) and spinal-cord homogenate (SC-H), whereas AA was induced by CFA only. Naive rats served as controls (n = 9 for each group). Two weeks after inoculation, animals were sacrificed, and brains were removed and processed for metabolomic analysis by NMR spectroscopy or for immunohistochemistry. Interestingly, both inflammatory diseases caused similar, though not identical, changes in metabolites involved in regulation of brain cell size and membrane production: among the osmolytes, taurine and the neuronal marker, N-acetylaspartate, were decreased, and the astrocyte marker, myo-inositol, slightly increased in both inoculated groups compared with controls. Also ethanolamine-containing phospholipids, sources of inflammatory agents, and several glycolytic metabolites were increased in both inoculated groups. By contrast, the amino acids, aspartate and isoleucine, were less concentrated in CFA/SC-H and control vs. CFA rats. Our results suggest that inflammatory brain metabolite profiles may indicate the existence of either cerebral (EAE) or extra-cerebral (AA) inflammation. These inflammatory processes may act through distinct pathways that converge toward similar brain metabolic profiles. Our findings open new avenues for future studies aimed at demonstrating whether brain metabolic effects provoked by AA are pain/stress-mediated and/or due to the

  20. Preparation and evaluation of functional foods in adjuvant arthritis

    OpenAIRE

    Al-Okbi, S. Y.; Mohamed, D. A.

    2012-01-01

    Adjuvant arthritis is an animal model that closely resembles rheumatoid arthritis in humans. It is a successful working model used to study new anti-inflammatory agents. In previous studies (animal and clinical) we have shown that evening primrose oil, fish oil and the methanol extract of date fruits and fenugreek seeds have anti-inflammatory activity and that the methanol extract of dates has an antioxidant effect. Based on these studies, the aim of the present study was to prepare 7 functio...

  1. Renal Toxicity of Adjuvant Chemoradiotherapy With Cisplatin in Gastric Cancer

    International Nuclear Information System (INIS)

    Welz, Stefan; Hehr, Thomas; Kollmannsberger, Christian; Bokemeyer, Carsten; Belka, Claus; Budach, Wilfried

    2007-01-01

    Purpose: Adjuvant, 5-fluorouracil (5-FU)-based chemoradiotherapy for completely resected high-risk gastric adenocarcinoma has been shown to improve survival in a randomized Intergroup trial. However, the results still showed an unsatisfactory outcome. On the basis of previously reported results of a Phase II trial using a more aggressive, cisplatin-containing chemoradiotherapy schedule, we investigated the effects of this approach on long-term renal function. Patients and Methods: Between December 2000 and September 2003, 27 patients were treated at Tuebingen University in a Phase II multicenter trial investigating adjuvant chemoradiotherapy. The adjuvant chemoradiotherapy consisted of two cycles of adjuvant 5-FU, folinic acid, cisplatin (200 mg/m 2 ), and paclitaxel before and after radiotherapy (45 Gy in 1.8-Gy fractions) with daily concomitant 5-FU (225 mg/m 2 /24 h). A dose constraint of ≤12 Gy for 37.5% of the functional volume of both kidneys was used. Renal function was assessed by the changes in creatinine and creatinine clearance during follow-up. Results: The prescribed 45 Gy was administered to 100% of the patients, and the cumulative cisplatin dose was 200 mg/m 2 in 74% of all patients. In 89%, the constraints concerning the renal absorbed doses were met. The median follow-up for the creatinine and clearance values was 30 and 26 months, respectively. The creatinine values tended to worsen over time without reaching critical levels. We were unable to demonstrate a significant dose-response relationship for renal damage in the tested dose range. Conclusions: Using a dose constraint of ≤12 Gy for 37.5% of the functional volume of both kidneys appears to be safe at a median follow-up of 2 years for a cumulative cisplatin dose of 200 mg/m 2 administered before and after simultaneous 5-FU and radiotherapy

  2. AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial

    NARCIS (Netherlands)

    McElhaney, J.E.; Beran, J.; Devaster, J.M.; Esen, M.; Launay, O.; Leroux-Roels, G.; Ruiz-Palacios, G.M.; Essen, G.A. van; Caplanusi, A.; Claeys, C.; Durand, C.; Duval, X.; Idrissi, M. El; Falsey, A.R.; Feldman, G.; Frey, S.E.; Galtier, F.; Hwang, S.J.; Innis, B.L.; Kovac, M.; Kremsner, P.; McNeil, S.; Nowakowski, A.; Richardus, J.H.; Trofa, A.; Oostvogels, L.; Verheugt, F.W.; et al.,

    2013-01-01

    BACKGROUND: We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. METHODS: We did a randomised trial in 15 countries worldwide during the 2008-09 (year 1) and 2009-10 (year 2) influenza seasons.

  3. Efficacy and tolerability of short-term specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A (MPL) for children and adolescents.

    Science.gov (United States)

    Drachenberg, K J; Heinzkill, M; Urban, E; Woroniecki, S R

    2003-01-01

    Specific immunotherapy (SIT) with pollen allergoids formulated with the Th1-inducing adjuvant 3-deacylated monophosphoryl lipid A (MPL adjuvant, Corixa) has shown good efficacy and tolerability in the treatment of pollen allergies in adults. The aim of this study was to evaluate this treatment in children and adolescents aged 6-17 years old who were sensitive to grass/rye or tree pollens. An open, multicenter study was performed using 90 children and adolescents. The patients received four subcutaneous injections of grass/rye (n = 64) or tree pollen allergoids (n = 26) adsorbed to L-tyrosine and containing MPL adjuvant. Efficacy was measured by symptom and medication scoring, skin prick test reactivity and IgG/IgE antibody responses. Tolerability was monitored by recording adverse events. Both grass/rye and tree pollen treatment groups showed significant reductions in symptom scores and anti-allergic medication use compared with the previous pollen seasons (p allergoids adsorbed to L-tyrosine and with MPL adjuvant was shown to be effective with good tolerability. The treatment compared favorably with previous studies in adults.

  4. The Use of Xanthan Gum as Vaccine Adjuvant: An Evaluation of Immunostimulatory Potential in BALB/c Mice and Cytotoxicity In Vitro

    Directory of Open Access Journals (Sweden)

    Rodrigo Andrade Schuch

    2017-01-01

    Full Text Available The successful production of new, safe, and effective vaccines that generate immunological memory is directly related to adjuvant feature, which is responsible for increasing and/or modulating the immune response. Several compounds display adjuvant activity, including carbohydrates. These compounds play important roles in the immune response, as well as having biocompatible properties in vaccine formulations. One such carbohydrate is xanthan gum, a polysaccharide that is produced by the plant-pathogenic bacterium Xanthomonas spp., which has adjuvant attributes. This study evaluated the immune response induced by xanthan gum associated with ovalbumin in BALB/c mice, which were subcutaneously immunized, in terms of antibody production (IgG1, IgG2a, IgG2b, and IgG3, and assessed the levels of IFN-γ in the splenocyte culture using indirect ELISA. Furthermore, we investigated in vitro cytotoxicity of xanthan in the embryo fibroblasts cell line of the NIH/3T3 mouse by MTT assay and propidium iodide uptake assay. The mice immunized with ovalbumin plus xanthan gum exhibited higher antibody IgG1 responses than control groups. Furthermore, the xanthan polysaccharide was capable of increasing the immunogenicity of antigens by producing IFN-γ and did not exhibit cytotoxicity effects in NIH/3T3 mouse fibroblast cells, considered a promising candidate for vaccine adjuvant.

  5. The Use of Xanthan Gum as Vaccine Adjuvant: An Evaluation of Immunostimulatory Potential in BALB/c Mice and Cytotoxicity In Vitro.

    Science.gov (United States)

    Schuch, Rodrigo Andrade; Oliveira, Thaís Larré; Collares, Thaís Farias; Monte, Leonardo Garcia; Inda, Guilherme Roig; Dellagostin, Odir Antonio; Vendruscolo, Claire Tondo; Moreira, Angelita da Silveira; Hartwig, Daiane Drawanz

    2017-01-01

    The successful production of new, safe, and effective vaccines that generate immunological memory is directly related to adjuvant feature, which is responsible for increasing and/or modulating the immune response. Several compounds display adjuvant activity, including carbohydrates. These compounds play important roles in the immune response, as well as having biocompatible properties in vaccine formulations. One such carbohydrate is xanthan gum, a polysaccharide that is produced by the plant-pathogenic bacterium Xanthomonas spp., which has adjuvant attributes. This study evaluated the immune response induced by xanthan gum associated with ovalbumin in BALB/c mice, which were subcutaneously immunized, in terms of antibody production (IgG1, IgG2a, IgG2b, and IgG3), and assessed the levels of IFN- γ in the splenocyte culture using indirect ELISA. Furthermore, we investigated in vitro cytotoxicity of xanthan in the embryo fibroblasts cell line of the NIH/3T3 mouse by MTT assay and propidium iodide uptake assay. The mice immunized with ovalbumin plus xanthan gum exhibited higher antibody IgG1 responses than control groups. Furthermore, the xanthan polysaccharide was capable of increasing the immunogenicity of antigens by producing IFN- γ and did not exhibit cytotoxicity effects in NIH/3T3 mouse fibroblast cells, considered a promising candidate for vaccine adjuvant.

  6. Adjuvant Activity of Poly-ε-caprolactone/Chitosan Nanoparticles Characterized by Mast Cell Activation and IFN-γ and IL-17 Production.

    Science.gov (United States)

    Jesus, Sandra; Soares, Edna; Borchard, Gerrit; Borges, Olga

    2018-01-02

    Polymeric nanoparticles (NPs) are extremely attractive vaccine adjuvants, able to promote antigen delivery and in some instances, exert intrinsic immunostimulatory properties that enhance antigen specific humoral and cellular immune responses. The poly-ε-caprolactone (PCL)/chitosan NPs were designed with the aim of being able to combine the properties of the 2 polymers in the preparation of an adjuvant for the hepatitis B surface antigen (HBsAg). This article reports important results of an in vitro mechanistic study and immunization studies with HBsAg associated with different concentrations of the nanoparticles. The results revealed that PCL/chitosan NPs promoted mast cell (MC) activation (β-hexosaminidase release) and that its adjuvant effect is not mediated by the TNF-α secretion. Moreover, we demonstrated that HBsAg loaded PCL/chitosan NPs, administered through the subcutaneous (SC) route, were able to induce higher specific antibody titers without increasing IgE when compared to a commercial vaccine, and that the IgG titers are nanoparticle-dose dependent. The results also revealed the NPs' capability to promote a cellular immune response against HBsAg, characterized by the production of IFN-γ and IL-17. These results demonstrated that PCL/chitosan NPs are a good hepatitis B antigen adjuvant, with direct influence on the intensity and type of the immune response generated.

  7. Structurally well-defined macrophage activating factor derived from vitamin D3-binding protein has a potent adjuvant activity for immunization.

    Science.gov (United States)

    Yamamoto, N; Naraparaju, V R

    1998-06-01

    Freund's adjuvant produced severe inflammation that augments development of antibodies. Thus, mixed administration of antigens with adjuvant was not required as long as inflammation was induced in the hosts. Since macrophage activation for phagocytosis and antigen processing is the first step of antibody development, inflammation-primed macrophage activation plays a major role in immune development. Therefore, macrophage activating factor should act as an adjuvant for immunization. The inflammation-primed macrophage activation process is the major macrophage activating cascade that requires participation of serum vitamin D3-binding protein (DBP; human DBP is known as Gc protein) and glycosidases of B and T lymphocytes. Stepwise incubation of Gc protein with immobilized beta-galactosidase and sialidase efficiently generated the most potent macrophage activating factor (designated GcMAF) we have ever encountered. Administration of GcMAF (20 or 100 pg/mouse) resulted in stimulation of the progenitor cells for extensive mitogenesis and activation of macrophages. Administration of GcMAF (100 pg/mouse) along with immunization of mice with sheep red blood cells (SRBC) produced a large number of anti-SRBC antibody secreting splenic cells in 2-4 days. Thus, GcMAF has a potent adjuvant activity for immunization. Although malignant tumours are poorly immunogenic, 4 days after GcMAF-primed immunization of mice with heat-killed Ehrlich ascites tumour cells, the ascites tumour was no longer transplantable in these mice.

  8. Factors Affecting Adjuvant Therapy in Stage III Pancreatic Cancer—Analysis of the National Cancer Database

    Directory of Open Access Journals (Sweden)

    Mridula Krishnan

    2017-08-01

    Full Text Available Background: Adjuvant therapy after curative resection is associated with survival benefit in stage III pancreatic cancer. We analyzed the factors affecting the outcome of adjuvant therapy in stage III pancreatic cancer and compared overall survival with different modalities of adjuvant treatment. Methods: This is a retrospective study of patients with stage III pancreatic cancer listed in the National Cancer Database (NCDB who were diagnosed between 2004 and 2012. Patients were stratified based on adjuvant therapy they received. Unadjusted Kaplan-Meier and multivariable Cox regression analysis were performed. Results: We analyzed a cohort included 1731 patients who were recipients of adjuvant therapy for stage III pancreatic cancer within the limits of our database. Patients who received adjuvant chemoradiation had the longest postdiagnosis survival time, followed by patients who received adjuvant chemotherapy, and finally patients who received no adjuvant therapy. On multivariate analysis, advancing age and patients with Medicaid had worse survival, whereas Spanish origin and lower Charlson comorbidity score had better survival. Conclusions: Our study is the largest trial using the NCDB addressing the effects of adjuvant therapy specifically in stage III pancreatic cancer. Within the limits of our study, survival benefit with adjuvant therapy was more apparent with longer duration from date of diagnosis.

  9. Analysis of adjuvant treatment with chemoradiation in gastric cancer

    International Nuclear Information System (INIS)

    Fallas Solis, Elias

    2008-01-01

    The Hospital San Juan de Dios has analyzed the benefit of patients with gastric cancer who undergo surgery after receiving adjuvant chemoradiation. A retrospective study was performed reviewing records of patients during the period 1 January 2001 to December 31, 2005. These patients have been discharged with a diagnosis of gastric cancer and have received a complete resection with curative gastric malignancy and adjuvant chemoradiation according to the protocol established by Dr. MacDonald. In the study 0116. 743 patients were discharged to Hospital San Juan de Dios, 1 in 20 has been possible to diagnose gastric cancer at early stages for a total of 28 patients. The results obtained were compared at the Hospital San Juan de Dios with those published by Dr. MacDonald. The over-life of 3 years in the chemoradiation group in Hospital San Juan de Dios has been of 42.9% and 50% in the study MacDonald. The group that has not received adjuvant the over-life in the same period has been of 20 % in HSJD and 41% in the study MacDonald, being lower percentage of patients with this over-life, but greater range of difference. [es

  10. Adjuvant chemotherapy compliance is not superior after thoracoscopic lobectomy

    DEFF Research Database (Denmark)

    Licht, Peter B; Schytte, Tine; Jakobsen, Erik

    2014-01-01

    BACKGROUND: It is generally assumed that patient compliance with adjuvant chemotherapy is superior after video-assisted thoracoscopic surgery compared with open lobectomy for non-small cell lung cancer (NSCLC). The level of evidence for this assumption, however, is limited to single-institution, ......BACKGROUND: It is generally assumed that patient compliance with adjuvant chemotherapy is superior after video-assisted thoracoscopic surgery compared with open lobectomy for non-small cell lung cancer (NSCLC). The level of evidence for this assumption, however, is limited to single...... adjuvant chemotherapy and 121 (38.7%) completed all four cycles. Ordinal logistic regression revealed that chemotherapy compliance (none, partial, and full chemotherapy) was significantly reduced by the patient's age (p....02). No significant difference between video-assisted thoracoscopic surgery and thoracotomy was seen regarding chemotherapy compliance (p=0.17), number of chemotherapy cycles (p=0.60), or time from surgery to chemotherapy (p = 0.41). CONCLUSIONS: Complete national data do not support the widespread assumption...

  11. Antinociceptive effect of chlorphenesin carbamate in adjuvant arthritic rats.

    Science.gov (United States)

    Okuyama, S; Aihara, H

    1987-02-01

    The antinociceptive effect of chlorphenesin carbamate (CPC) and mephenesin were examined in adjuvant arthritic rats. In the behavioral study, CPC (100-400 mg/kg, p.o.) but not mephenesin (100-400 mg/kg, p.o.) had a dose-dependent antinociceptive effect, determined using the flexion test. In the electrophysiological study, CPC (25-50 mg/kg, i.v.) but not mephenesin (50 mg/kg, i.v.) depressed the evoked neuronal responses of nociceptive neurons in the ventrobasal thalamus (VB), while the evoked responses of non-nociceptive neurons were not depressed by either CPC (50 mg/kg, i.v.) or mephenesin (50 mg/kg, i.v.). The spontaneous firings of the VB nociceptive neurons were depressed by both CPC (50 mg/kg, i.v.) and mephenesin (50 mg/kg, i.v.). However, mephenesin (50 mg/kg, i.v.) but not CPC (50 mg/kg, i.v.) also depressed the spontaneous firings of the mesencephalic reticular formation (RF), in these adjuvant arthritic rats. These results indicate that CPC but not mephenesin, has an antinociceptive action in adjuvant arthritic rats.

  12. Liposomal preparations of muramyl glycopeptides as immunomodulators and adjuvants.

    Science.gov (United States)

    Turánek, Jaroslav; Ledvina, Miroslav; Kasná, Andrea; Vacek, Antonín; Hríbalova, Vera; Krejcí, Josef; Miller, Andrew D

    2006-04-12

    The need for safe and structurally defined immunomodulators and adjuvants is increasing in connection with the recently observed marked increase in the prevalence of pathological conditions characterized by immunodeficiency. Important groups of such compounds are muramyl glycopeptides, analogs of muramyl dipeptide (MDP), glucosaminyl-muramyl dipeptide (GMDP), and desmuramylpeptides. We have designed and synthesized new types of analogs with changes in both the sugar and the peptide parts of the molecule that show a high immunostimulating and adjuvant activity and suppressed adverse side effects. The introduction of lipophilic residues has also improved their incorporation into liposomes, which represent a suitable drug carrier. The proliposome-liposome method is based on the conversion of the initial proliposome preparation into liposome dispersion by dilution with the aqueous phase. The description of a home-made stirred thermostated cell and its link-up with a liquid delivery system for a rapid and automated preparation of multilamellar liposomes at strictly controlled conditions (sterility, temperature, dilution rate and schedule) is presented. The cell has been designed for laboratory-scale preparation of liposomes (300-1000 mg of phospholipid per run) in a procedure taking less than 90 min. The method can be readily scaled up. Examples of adjuvant and immunostimulatory effect of liposomal preparation in mice model will be presented.

  13. Comparison of the adjuvant activity of aluminum hydroxide and calcium phosphate on the antibody response towards Bothrops asper snake venom.

    Science.gov (United States)

    Olmedo, Hidekel; Herrera, María; Rojas, Leonardo; Villalta, Mauren; Vargas, Mariángela; Leiguez, Elbio; Teixeira, Catarina; Estrada, Ricardo; Gutiérrez, José María; León, Guillermo; Montero, Mavis L

    2014-01-01

    The adjuvanticity of aluminum hydroxide and calcium phosphate on the antibody response in mice towards the venom of the snake Bothrops asper was studied. It was found that, in vitro, most of the venom proteins are similarly adsorbed by both mineral salts, with the exception of some basic phospholipases A2, which are better adsorbed by calcium phosphate. After injection, the adjuvants promoted a slow release of the venom, as judged by the lack of acute toxicity when lethal doses of venom were administered to mice. Leukocyte recruitment induced by the venom was enhanced when it was adsorbed on both mineral salts; however, venom adsorbed on calcium phosphate induced a higher antibody response towards all tested HPLC fractions of the venom. On the other hand, co-precipitation of venom with calcium phosphate was the best strategy for increasing: (1) the capacity of the salt to couple venom proteins in vitro; (2) the venom ability to induce leukocyte recruitment; (3) phagocytosis by macrophages; and (4) a host antibody response. These findings suggest that the chemical nature is not the only one determining factor of the adjuvant activity of mineral salts.

  14. Immunogenicity of a virosomally-formulated Plasmodium falciparum GLURP-MSP3 chimeric protein-based malaria vaccine candidate in comparison to adjuvanted formulations

    Directory of Open Access Journals (Sweden)

    Tamborrini Marco

    2011-12-01

    Full Text Available Abstract Background In clinical trials, immunopotentiating reconstituted influenza virosomes (IRIVs have shown great potential as a versatile antigen delivery platform for synthetic peptides derived from Plasmodium falciparum antigens. This study describes the immunogenicity of a virosomally-formulated recombinant fusion protein comprising domains of the two malaria vaccine candidate antigens MSP3 and GLURP. Methods The highly purified recombinant protein GMZ2 was coupled to phosphatidylethanolamine and the conjugates incorporated into the membrane of IRIVs. The immunogenicity of this adjuvant-free virosomal formulation was compared to GMZ2 formulated with the adjuvants Montanide ISA 720 and Alum in three mouse strains with different genetic backgrounds. Results Intramuscular injections of all three candidate vaccine formulations induced GMZ2-specific antibody responses in all mice tested. In general, the humoral immune response in outbred NMRI mice was stronger than that in inbred BALB/c and C57BL/6 mice. ELISA with the recombinant antigens demonstrated immunodominance of the GLURP component over the MSP3 component. However, compared to the Al(OH3-adjuvanted formulation the two other formulations elicited in NMRI mice a larger proportion of anti-MSP3 antibodies. Analyses of the induced GMZ2-specific IgG subclass profiles showed for all three formulations a predominance of the IgG1 isotype. Immune sera against all three formulations exhibited cross-reactivity with in vitro cultivated blood-stage parasites. Immunofluorescence and immunoblot competition experiments showed that both components of the hybrid protein induced IgG cross-reactive with the corresponding native proteins. Conclusion A virosomal formulation of the chimeric protein GMZ2 induced P. falciparum blood stage parasite cross-reactive IgG responses specific for both MSP3 and GLURP. GMZ2 thus represents a candidate component suitable for inclusion into a multi-valent virosomal

  15. Gamma ray sterilization of delta inulin adjuvant particles (Advax™) makes minor, partly reversible structural changes without affecting adjuvant activity

    Science.gov (United States)

    Cooper, P. D.; Barclay, T. G.; Ginic-Markovic, M.; Petrovsky, N.

    2014-01-01

    We earlier identified a developmental series of seven isoforms/polymorphs of microparticulate inulin by comparing non-covalent bonding strengths. Their pharmaceutical utility lies in modulation of cellular immunity, exploited as vaccine adjuvants (Advax™) especially for delta inulin (DI). As such particles cannot be sterilized by filtration we explore the effect of 60Co gamma radiation (GR) on inulin isoforms, particularly DI. Its adjuvant activity and overt physical properties were unaffected by normal GR sterilizing doses (up to 25 kGy). Heating irradiated isoform suspensions near their critical dissolution temperature revealed increased solubility deduced to reflect a single lethal event in one component of a multi-component structure. Local oxidative effects of GR on DI were not found. The observed DI loss was almost halved by re-annealing at the critical temperature: surviving inulin chains apparently reassemble into smaller amounts of the original type of structure. Colorimetric tetrazolium assay revealed increases in reducing activity after GR of raw inulin powder, which yielded DI with normal physical properties but only 25% normal recovery yet 4× normal reducing ability, implying final retention of some GR-changed inulin chains. These findings suggest minimal inulin chain cleavage and confirm that GR may be a viable strategy for terminal sterilization of microparticulate inulin adjuvants. PMID:24342245

  16. Cost-utility analysis of adjuvant goserelin (Zoladex and adjuvant chemotherapy in premenopausal women with breast cancer

    Directory of Open Access Journals (Sweden)

    Cheng Tsui

    2012-01-01

    Full Text Available Abstract Background Increased health care costs have made it incumbent on health-care facilities and physicians to demonstrate both clinical and cost efficacy when recommending treatments. Though studies have examined the cost-effectiveness of adjuvant goserelin with radiotherapy for locally advanced prostate cancer, few have compared the cost-effectiveness of adjuvant goserelin to adjuvant chemotherapy alone in premenopausal breast cancer. Methods In this retrospective study at one hospital, the records of 152 patients with stage Ia to IIIa ER + breast cancer who received goserelin or chemotherapy were reviewed. Survival analysis was assessed by the Kaplan-Meier method. Patients were interviewed to evaluate their quality of life using the European Organization for Research and Treatment Quality of Life questionnaire (EORTC-QLQ-C30, version 4.0, and to obtain the utility value by the standard gamble (SG and visual scale (VS methods. Total medical cost was assessed from the (National Health Insurance NHI payer's perspective. Results Survival at 11 years was significantly better in the groserelin group (P Conclusions Goserelin therapy results in better survival and higher utility-weighted life-years, and is more cost-effective than TC or TEC chemotherapy.

  17. Adjuvant endocrine and chemotherapy for early breast cancer

    International Nuclear Information System (INIS)

    Henderson, I. Craig

    1996-01-01

    Objective: Present the results of the 1995 World Overview which will be held in Oxford England two weeks before ASTRO. Discuss the interpretation and application of these results. Review current research topics on the use of adjuvant endocrine and chemotherapy for early breast cancer. The survival benefits from adjuvant chemotherapy in premenopausal women and adjuvant tamoxifen in postmenopausal women are well established. Each will reduce the annual odds of death by about 25% resulting in a 10 year survival difference of 8-10%. By the time of this presentation, the results of the 1995 Adjuvant Therapy Overview should be with 10+ years of follow-up, and if possible these will be summarized. Current efforts to improve on previous results are focused on the following areas: Optimal chemotherapy dose. Decreasing dose will compromise patient survival. It is not as certain that increasing dose will have as much impact in improving survival. The NSABP was unable to demonstrate an improvement in survival by modestly increasing the dose of cyclophosphamide alone. However, recent results of a Canadian study of CEF (cyclophosphamide, epidoxorubicin, and 5-fluorouracil) and an Intergroup trial of an intense 16 week polychemotherapy program keep alive the possibility that dose escalation is still a very important question. An NSABP trial evaluating even greater cyclophosphamide dose escalation, an Intergroup evaluation of different doxorubicin doses, and two Intergroup trials evaluating very high dose chemotherapy and bone marrow transplantation should provide definitive evidence regarding the importance of dose. Drug sequence. A study from Milan suggests that initial treatment with single agent doxorubicin followed by CMF will be superior to alternating doxorubicin and CMF. This has not been confirmed yet, and the reason for increased benefit from such a sequence is not entirely clear. This concept is being explored further in an Intergroup trial comparing four cycles of

  18. Development of a minimal saponin vaccine adjuvant based on QS-21

    Science.gov (United States)

    Fernández-Tejada, Alberto; Chea, Eric K.; George, Constantine; Pillarsetty, Nagavarakishore; Gardner, Jeffrey R.; Livingston, Philip O.; Ragupathi, Govind; Lewis, Jason S.; Tan, Derek S.; Gin, David Y.

    2014-07-01

    Adjuvants are materials added to vaccines to enhance the immunological response to an antigen. QS-21 is a natural product adjuvant under investigation in numerous vaccine clinical trials, but its use is constrained by scarcity, toxicity, instability and an enigmatic molecular mechanism of action. Herein we describe the development of a minimal QS-21 analogue that decouples adjuvant activity from toxicity and provides a powerful platform for mechanistic investigations. We found that the entire branched trisaccharide domain of QS-21 is dispensable for adjuvant activity and that the C4-aldehyde substituent, previously proposed to bind covalently to an unknown cellular target, is also not required. Biodistribution studies revealed that active adjuvants were retained preferentially at the injection site and the nearest draining lymph nodes compared with the attenuated variants. Overall, these studies have yielded critical insights into saponin structure-function relationships, provided practical synthetic access to non-toxic adjuvants, and established a platform for detailed mechanistic studies.

  19. Mast cells contribute to the mucosal adjuvant effect of CTA1-DD after IgG-complex formation.

    Science.gov (United States)

    Fang, Yu; Larsson, Lisa; Mattsson, Johan; Lycke, Nils; Xiang, Zou

    2010-09-01

    Mast cell activation is one of the most dramatic immune-mediated responses the body can encounter. In the worst scenario (i.e., anaphylaxis), this response is fatal. However, the importance of mast cells as initiators and effectors of both innate and adaptive immunity in healthy individuals has recently been appreciated. It was reported that mast cell activation can be used as an adjuvant to promote Ag-specific humoral immune responses upon vaccination. In this study, we have used a clinically relevant mucosal adjuvant, cholera toxin A1 subunit (CTA1)-DD, which is a fusion protein composed of CTA1, the ADP-ribosylating part of cholera toxin, and DD, two Ig-binding domains derived from Staphylococcus aureus protein A. CTA1-DD in combination with polyclonal IgG induced degranulation and production of TNF-alpha from mouse mast cells. Furthermore, CTA1-DD and polyclonal IgG complex induced mast cell degranulation in mouse skin tissue and nasal mucosa. We also found that intranasal immunization with hapten (4-hydroxy-3-nitrophenyl) acetyl (NP) coupled to chicken gammaglobulin admixed with CTA1-DD complexed with polyclonal IgG greatly enhanced serum IgG anti-NP Ab responses and stimulated higher numbers of NP-specific plasma cells in the bone marrow as compared with that observed in mice immunized with NP-chicken gammaglobulin with CTA1-DD alone. This CTA1-DD/IgG complex-mediated enhancement was mast cell dependent because it was absent in mast cell-deficient Kit(W-sh/W-sh) mice. In conclusion, our data suggest that a clinically relevant adjuvant, CTA1-DD, exerts additional augmenting effects through activation of mucosal mast cells, clearly demonstrating that mast cells could be further exploited for improving the efficacy of mucosal vaccines.

  20. Selective Thrombolysis in Acute Deep Vein Thrombosis: Evaluation of Adjuvant Therapy In Vivo

    International Nuclear Information System (INIS)

    Roy, Sumit; Brosstad, Frank; Sakariassen, Kjell S.

    1999-01-01

    Purpose: To evaluate in a porcine model of acute deep vein thrombosis (DVT) the efficacy of dalteparin and antithrombin with respect to heparin for local adjuvant therapy during selective thrombolysis, and the utility of nitroglycerin and iloprost as heparin supplements. Methods: DVT was induced in both hind limbs using a previously described technique (n = 20). Thirty minutes later, the animal was heparinized (2500 IU IV), and bilateral sequestrated thrombolysis was performed using 8 mg alteplase: both external iliac veins were endoluminally occluded with Swan-Ganz catheters, and a multi-sideport infusion wire coaxially introduced through each catheter and advanced into the ipsilateral popliteal vein. In the control limbs, tissue plasminogen activator (tPA) 8 mg was injected as 0.8-ml boluses at 3-min intervals for 2 hr as a 0.25-mg/ml solution containing heparin 50 IU/ml (n 20). On the contralateral side, heparin was substituted with either dalteparin 50 IU/ml (n = 5) or antithrombin 12.5 IU/ml (n = 5), or supplemented with either nitroglycerin 0.075 mg/ml (n = 5) or iloprost (150 ng/ml) (n = 5). Blood samples were taken at predetermined intervals to measure the activated partial thromboplastin time (aPTT), prothrombin time (PT), and fibrinogen concentration. At autopsy, the thrombus mass in the iliofemoral veins was measured, and the extent of residual thrombosis in the venous tributaries graded at four sites. Results: Bilateral thrombolysis was successfully completed in all animals. The median thrombus mass in the iliofemoral veins after thrombolysis was 0.48 g (range 0.06-1.58 g), 0.95 g (0.59-1.29 g), 0.74 g (0.52-0.96 g), and 0.29 g (0.0-0.77 g) for dalteparin, antithrombin, iloprost, and nitroglycerin respectively, as compared with 0.53 g (0.18-0.88 g) (p = 0.69), 0.97 g (0.46-1.15 g) (p = 0.69), 0.53 g (0.48-1.10 g) (p = 0.69), and 0.18 g (0.13-1.04 g) (p = 0.5) for the respective controls. Likewise, the severity of residual thrombosis in the venous

  1. Co-localization of a CD1d-binding glycolipid with a radiation-attenuated sporozoite vaccine in LN-resident DCs for a robust adjuvant effect

    Science.gov (United States)

    Li, Xiangming; Kawamura, Akira; Andrews, Chasity D.; Miller, Jessica L.; Wu, Douglass; Tsao, Tiffany; Zhang, Min; Oren, Deena; Padte, Neal N.; Porcelli, Steven A.; Wong, Chi-Huey; Kappe, Stefan H. I.; Ho, David D.; Tsuji, Moriya

    2015-01-01

    A CD1d-binding glycolipid, α-Galactosylceramide (αGalCer), activates invariant natural killer T (iNKT) cells and acts as an adjuvant. We previously identified a fluorinated phenyl ring-modified αGalCer analog, 7DW8-5, displaying nearly 100-fold stronger CD1d binding affinity. In the present study, 7DW8-5 was found to exert a more potent adjuvant effect than αGalCer for a vaccine based on radiation-attenuated sporozoites (RAS) of a rodent malaria parasite, Plasmodium yoelii, also referred to as irradiated P. yoelii sporozoites (IrPySpz). 7DW8-5 had a superb adjuvant effect only when the glycolipid and IrPySpz were conjointly administered intramuscularly (i.m.). Therefore, we evaluated the impact of distinctly different biodistribution patterns of αGalCer and 7DW8-5 on their respective adjuvant activities. While both glycolipids induce a similar cytokine response in sera of mice injected intravenously, after i.m. injection, αGalCer induces a systemic cytokine response, whereas 7DW8-5 is locally trapped by CD1d expressed by dendritic cells (DCs) in draining lymph nodes (dLNs). Moreover, the i.m. co-administration of 7DW8-5 with IrPySpz results in the recruitment of DCs to dLNs and the activation and maturation of DCs. These events cause the potent adjuvant effect of 7DW8-5, resulting in the enhancement of the CD8+ T-cell response induced by IrPySpz, and, ultimately, improved protection against malaria. Our study is the first to show that the co-localization of a CD1d-binding iNKT-cell stimulatory glycolipid and a vaccine, like RAS, in dLN-resident DCs upon i.m. conjoin administration governs the potency of the adjuvant effect of the glycolipid. PMID:26254338

  2. Colocalization of a CD1d-Binding Glycolipid with a Radiation-Attenuated Sporozoite Vaccine in Lymph Node-Resident Dendritic Cells for a Robust Adjuvant Effect.

    Science.gov (United States)

    Li, Xiangming; Kawamura, Akira; Andrews, Chasity D; Miller, Jessica L; Wu, Douglass; Tsao, Tiffany; Zhang, Min; Oren, Deena; Padte, Neal N; Porcelli, Steven A; Wong, Chi-Huey; Kappe, Stefan H I; Ho, David D; Tsuji, Moriya

    2015-09-15

    A CD1d-binding glycolipid, α-Galactosylceramide (αGalCer), activates invariant NK T cells and acts as an adjuvant. We previously identified a fluorinated phenyl ring-modified αGalCer analog, 7DW8-5, displaying nearly 100-fold stronger CD1d binding affinity. In the current study, 7DW8-5 was found to exert a more potent adjuvant effect than αGalCer for a vaccine based on radiation-attenuated sporozoites of a rodent malaria parasite, Plasmodium yoelii, also referred to as irradiated P. yoelii sporozoites (IrPySpz). 7DW8-5 had a superb adjuvant effect only when the glycolipid and IrPySpz were conjointly administered i.m. Therefore, we evaluated the effect of distinctly different biodistribution patterns of αGalCer and 7DW8-5 on their respective adjuvant activities. Although both glycolipids induce a similar cytokine response in sera of mice injected i.v., after i.m. injection, αGalCer induces a systemic cytokine response, whereas 7DW8-5 is locally trapped by CD1d expressed by dendritic cells (DCs) in draining lymph nodes (dLNs). Moreover, the i.m. coadministration of 7DW8-5 with IrPySpz results in the recruitment of DCs to dLNs and the activation and maturation of DCs. These events cause the potent adjuvant effect of 7DW8-5, resulting in the enhancement of the CD8(+) T cell response induced by IrPySpz and, ultimately, improved protection against malaria. Our study is the first to show that the colocalization of a CD1d-binding invariant NK T cell-stimulatory glycolipid and a vaccine, like radiation-attenuated sporozoites, in dLN-resident DCs upon i.m. conjoint administration governs the potency of the adjuvant effect of the glycolipid. Copyright © 2015 by The American Association of Immunologists, Inc.

  3. Interferon alpha for the adjuvant treatment of cutaneous melanoma.

    Science.gov (United States)

    Mocellin, Simone; Lens, Marko B; Pasquali, Sandro; Pilati, Pierluigi; Chiarion Sileni, Vanna

    2013-06-18

    Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high-risk cutaneous melanoma. However, the survival advantage associated with this treatment is unclear, especially in terms of overall survival. Thus, adjuvant interferon is not universally considered a gold standard treatment by all oncologists. To assess the disease-free survival and overall survival effects of interferon alpha as adjuvant treatment for people with high-risk cutaneous melanoma. We searched the following databases up to August 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, issue 8), MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), and LILACS (from 1982). We also searched trials databases in 2011, and proceedings of the ASCO annual meeting from 2000 to 2011. We checked the reference lists of selected articles for further references to relevant trials. We included only randomised controlled trials (RCTs) comparing interferon alpha to observation (or any other treatment) for the postoperative (adjuvant) treatment of patients with high-risk skin melanoma, that is, people with regional lymph node metastasis (American Joint Committee on Cancer (AJCC) TNM (tumour, lymph node, metastasis) stage III) undergoing radical lymph node dissection, or people without nodal disease but with primary tumour thickness greater than 1 mm (AJCC TNM stage II). Two authors extracted data, and a third author independently verified the extracted data. The main outcome measure was the hazard ratio (HR), which is the ratio of the risk of the event occurring in the treatment arm (adjuvant interferon) compared to the control arm (no adjuvant interferon). The survival data were either entered directly into Review Manager (RevMan) or extrapolated from Kaplan-Meier plots and then entered into RevMan. Based on the presence of between-study heterogeneity, we applied a fixed-effect or random-effects model for calculating the pooled estimates

  4. A caprine herpesvirus 1 vaccine adjuvanted with MF59™ protects against vaginal infection and interferes with the establishment of latency in goats.

    Directory of Open Access Journals (Sweden)

    Mariarosaria Marinaro

    Full Text Available The immunogenicity and the efficacy of a beta-propiolactone-inactivated caprine herpesvirus 1 (CpHV-1 vaccine adjuvanted with MF59™ were tested in goats. Following two subcutaneous immunizations, goats developed high titers of CpHV-1-specific serum and vaginal IgG and high serum virus neutralization (VN titers. Peripheral blood mononuclear cells (PBMC stimulated in vitro with inactivated CpHV-1 produced high levels of soluble IFN-gamma and exhibited high frequencies of IFN-gamma producing cells while soluble IL-4 was undetectable. On the other hand, control goats receiving the inactivated CpHV-1 vaccine without adjuvant produced only low serum antibody responses. A vaginal challenge with virulent CpHV-1 was performed in all vaccinated goats and in naïve goats to assess the efficacy of the two vaccines. Vaginal disease was not detected in goats vaccinated with inactivated CpHV-1 plus MF59™ and these animals had undetectable levels of infectious challenge virus in their vaginal washes. Goats vaccinated with inactivated CpHV-1 in the absence of adjuvant exhibited a less severe disease when compared to naïve goats but shed titers of challenge virus that were similar to those of naïve goats. Detection and quantitation of latent CpHV-1 DNA in sacral ganglia in challenged goats revealed that the inactivated CpHV-1 plus MF59™ vaccine was able to significantly reduce the latent viral load when compared either to the naïve goats or to the goats vaccinated with inactivated CpHV-1 in the absence of adjuvant. Thus, a vaccine composed of inactivated CpHV-1 plus MF59™ as adjuvant was strongly immunogenic and induced effective immunity against vaginal CpHV-1 infection in goats.

  5. A Caprine Herpesvirus 1 Vaccine Adjuvanted with MF59™ Protects against Vaginal Infection and Interferes with the Establishment of Latency in Goats

    Science.gov (United States)

    Marinaro, Mariarosaria; Rezza, Giovanni; Del Giudice, Giuseppe; Colao, Valeriana; Tarsitano, Elvira; Camero, Michele; Losurdo, Michele; Buonavoglia, Canio; Tempesta, Maria

    2012-01-01

    The immunogenicity and the efficacy of a beta-propiolactone-inactivated caprine herpesvirus 1 (CpHV-1) vaccine adjuvanted with MF59™ were tested in goats. Following two subcutaneous immunizations, goats developed high titers of CpHV-1-specific serum and vaginal IgG and high serum virus neutralization (VN) titers. Peripheral blood mononuclear cells (PBMC) stimulated in vitro with inactivated CpHV-1 produced high levels of soluble IFN-gamma and exhibited high frequencies of IFN-gamma producing cells while soluble IL-4 was undetectable. On the other hand, control goats receiving the inactivated CpHV-1 vaccine without adjuvant produced only low serum antibody responses. A vaginal challenge with virulent CpHV-1 was performed in all vaccinated goats and in naïve goats to assess the efficacy of the two vaccines. Vaginal disease was not detected in goats vaccinated with inactivated CpHV-1 plus MF59™ and these animals had undetectable levels of infectious challenge virus in their vaginal washes. Goats vaccinated with inactivated CpHV-1 in the absence of adjuvant exhibited a less severe disease when compared to naïve goats but shed titers of challenge virus that were similar to those of naïve goats. Detection and quantitation of latent CpHV-1 DNA in sacral ganglia in challenged goats revealed that the inactivated CpHV-1 plus MF59™ vaccine was able to significantly reduce the latent viral load when compared either to the naïve goats or to the goats vaccinated with inactivated CpHV-1 in the absence of adjuvant. Thus, a vaccine composed of inactivated CpHV-1 plus MF59™ as adjuvant was strongly immunogenic and induced effective immunity against vaginal CpHV-1 infection in goats. PMID:22511971

  6. Use of chemical and biological adjuvants to achieve the optimum application of radiological techniques

    International Nuclear Information System (INIS)

    Azab, K.S.

    2010-01-01

    Nowadays, the optimization and attainment of maximum guarantee are representing the real challenge for the nuclear technology exercise. The Adjuvant techniques might be considered one of the available tactics for the developing, reducing risk and facilitating secure clearing of nuclear waste in the field of radiation technology applications. The history describes the belief that an adjuvant is required for immunity because the immune system evolved to respond to dangerous situations such as infections, and the presence of an adjuvant is the mechanism used to identify these situations. In immunology, an adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect. Adjuvants are coming increasingly into focus for vaccine developers since many novel split and subunit vaccines are insufficiently immunogenic on their own. Among the used today are alum (aluminum hydroxide) and Glycosyl ceramides. It is worth mentioning that manufacturers already had produced thousands of different adjuvants, for both industrial and agricultural purposes. Today, the agricultural and horticultural industries are being overwhelmed by adjuvant choices. Complete Freunds adjuvant is the adjuvant used in animal research studies of basic and applied immunology. (author)

  7. Human papilloma virus and survival of oropharyngeal cancer patients treated with surgery and adjuvant radiotherapy.

    Science.gov (United States)

    Broglie, Martina A; Soltermann, Alex; Haile, Sarah R; Huber, Gerhard F; Stoeckli, Sandro J

    2015-07-01

    Impact of p16 protein, a surrogate marker for human papilloma virus induced cancer, p53 and EGFR as well as clinical factors on survival in a patient cohort with oropharyngeal squamous cell carcinoma (OPSCC) treated by surgical resection and adjuvant radiotherapy (RT) ± concomitant chemotherapy (CT). This is a retrospective analysis of patient's charts and tumor tissue. 57 patients were consecutively included and their tumor tissue assembled on a tissue microarray following immunohistochemical analysis. Survival times were estimated by means of Kaplan-Meier analysis. The importance of clinical and immunohistochemical factors for outcome was estimated by cox proportional hazard models. With 88% 5-year overall survival, 91% 5-year disease-specific survival and 91% 5-year disease-free survival, respectively, we found excellent survival rates in this surgically treated patient cohort of mainly advanced OPSCC (93% AJCC stage III or IV). The only factors positively influencing survival were p16 overexpression as well as p53 negativity and even more pronounced the combination of those biomarkers. Survival analysis of patients classified into three risk categories according to an algorithm based on p16, smoking, T- and N-category revealed a low, intermediate and high-risk group with significant survival differences between the low and the high-risk group. Patients with OPSCC can be successfully treated by surgery and adjuvant RT ± CT with a clear survival benefit of p16 positive, p53 negative patients. We recommend considering a combination of immunohistochemical (p16, p53) and clinical factors (smoking, T- and N-category) for risk stratification.

  8. Nongenetically modified Lactococcus lactis-adjuvanted vaccination enhanced innate immunity against Helicobacter pylori.

    Science.gov (United States)

    Liu, Wei; Tan, Zhoulin; Liu, Hai; Zeng, Zhiqin; Luo, Shuanghui; Yang, Huimin; Zheng, Lufeng; Xi, Tao; Xing, Yingying

    2017-10-01

    Gram-positive enhancer matrix particles (GEM) produced by Lactococcus lactis can enhance vaccine-induced immune response. However, the mechanism under which this adjuvant mounts the efficacy of orally administered vaccines remains unexplored. We used a prophylactic mice model to investigate the mechanism of GEM-adjuvanted vaccination. Helicobacter pylori urease-specific antibody response was monitored and detected in murine serum by ELISA. Urease-specific splenic cytokine profile was examined. Gastric inflammatory responses were measured on day 43 or 71 by quantitative real-time PCR, flow cytometry and histology. We found that GEM enhanced the efficiency of oral H. pylori vaccine by promoting innate immunity. The vaccine CUE-GEM composed of GEM particles and recombinant antigen CTB-UE provided protection of immunized mice against H. pylori insult. The protective response was associated with induction of postimmunization gastritis and local Th1/Th17 cell-medicated immune response. We showed that innate inflammatory responses including neutrophil chemokines CXCL1-2, neutrophils, and antimicrobial proteins S100A8 and MUC1 were significantly elevated. Within all infected mice, S100A8 and MUC1 levels were negatively correlated with H. pylori burden. Strikingly, mice receiving GEM also show reduction of colonization, possibly through natural host response pathways to recruit CD4 + T cells and promote S100A8 expression. These findings suggest that GEM-based vaccine may impact Th1/Th17 immunity to orchestrate innate immune response against H. pylori infection. © 2017 John Wiley & Sons Ltd.

  9. Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

    Science.gov (United States)

    Tsen, Andrew R; Long, Patrick M; Driscoll, Heather E; Davies, Matthew T; Teasdale, Benjamin A; Penar, Paul L; Pendlebury, William W; Spees, Jeffrey L; Lawler, Sean E; Viapiano, Mariano S; Jaworski, Diane M

    2014-03-15

    Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors. © 2013 UICC.

  10. The St. Gallen Prize Lecture 2011: evolution of long-term adjuvant anti-hormone therapy: consequences and opportunities.

    Science.gov (United States)

    Jordan, V Craig; Obiorah, Ifeyinwa; Fan, Ping; Kim, Helen R; Ariazi, Eric; Cunliffe, Heather; Brauch, Hiltrud

    2011-10-01

    described not only the unique mechanism of selective ER modulator (SERM)-stimulated breast cancer growth, but also a new apoptotic biology of oestradiol action in breast cancer, following 5 years of anti-hormonal treatment. Oestradiol-induced apoptotic therapy is currently shown to be successful for the short-term treatment of metastatic ER positive breast cancer following exhaustive treatment with anti-hormones. The "oestrogen purge" concept is now being integrated into trials of long-term adjuvant anti-hormone therapy. The Study of Letrazole Extension (SOLE) trial employs "anti-hormonal drug holidays" so that a woman's own oestrogen may periodically purge and kill the nascent sensitized breast cancer cells that are developing. This is the translation of an idea first proposed at the 1992 St. Gallen Conference. Although tamoxifen is the first successful targeted therapy in cancer, the pioneering medicine is more than that. A study of the pharmacology of tamoxifen opened the door for a pioneering application in cancer chemoprevention and created a new drug group: the SERMs, with group members (raloxifene and lasofoxifene) approved for the treatment and prevention of osteoporosis with a simultaneous reduction of breast cancer risk. Thus, the combined strategies of long-term anti-hormone adjuvant therapy, targeted to the breast tumour ER, coupled with the expanding use of SERMs to prevent osteoporosis and prevent breast cancer as a beneficial side effect, have advanced patient survivorship significantly and promise to reduce breast cancer incidence. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Adjuvant radiotherapy for phyllodes tumor of the breast

    International Nuclear Information System (INIS)

    Chaney, Arthur W.; Pollack, Alan; Zagars, Gunar K.

    1997-01-01

    Purpose/Objective: The role of radiotherapy for the treatment of phyllodes tumors of the breast remains controversial. Adjuvant radiotherapy is often cited in the existing literature as not providing any benefit over surgical treatment alone. The data supporting this belief are anecdotal. There are also anecdotal reports that radiotherapy may have a role in cases wherein the risk of local failure is high. As with breast carcinomas, conservative surgery (wide local excision) for phyllodes tumors is associated with about a 50% local recurrence rate; diffuse or bulky disease and/or malignant histology are also associated with high local failure rates. We are unaware of any series that examines the role of adjuvant radiotherapy in the management of phyllodes tumor of the breast. We present here a retrospective study of eight patients so treated at MD Anderson Cancer Center. Materials and Methods: Eight patients have been treated with radiotherapy for non-metastatic phyllodes tumor of the breast at MD Anderson Cancer Center between December 1988 and August 1993. All patients were female; the median age was 43 years, with a range of 19 to 62 years. All patients presented with a breast mass, which was associated with pain in one patient, and was ulcerative in three. Results: Tumor size ranged from 3.5 to 16 cm, with a median diameter of 10.4 cm. Six patients had tumors in the upper outer quadrant, and two patients had upper inner tumors. Five patients had malignant tumors, two patients were classified as benign, and one was of indeterminate malignant potential. All five of the malignant tumors displayed stromal overgrowth on pathologic review. The remaining benign and indeterminate tumors lacked this feature. One patient with a benign tumor had a history of two prior recurrences. Primary surgery consisted of either lumpectomy in two patients or mastectomy in six patients. Axillary level I/II lymph node dissections were performed in 5 patients and no involvement was seen

  12. Endocrine effects of adjuvant letrozole + triptorelin compared with tamoxifen + triptorelin in premenopausal patients with early breast cancer.

    Science.gov (United States)

    Rossi, Emanuela; Morabito, Alessandro; De Maio, Ermelinda; Di Rella, Francesca; Esposito, Giuseppe; Gravina, Adriano; Labonia, Vincenzo; Landi, Gabriella; Nuzzo, Francesco; Pacilio, Carmen; Piccirillo, Maria Carmela; D'Aiuto, Giuseppe; D'Aiuto, Massimiliano; Rinaldo, Massimo; Botti, Gerardo; Gallo, Ciro; Perrone, Francesco; de Matteis, Andrea

    2008-01-10

    To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study). Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin +/- zoledronate. Serum 17-beta-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Delta4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. Median age was 44 years for both groups of patients. Letrozole + triptorelin (+/- zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.

  13. Enhancement of human immunodeficiency virus type 1-DNA vaccine potency through incorporation of T-helper 1 molecular adjuvants.

    Science.gov (United States)

    Calarota, Sandra A; Weiner, David B

    2004-06-01

    It is clear that the development of a safe and effective vaccine for human immunodeficiency virus type 1 (HIV-1) remains a crucial goal for controlling the acquired immunodeficiency syndrome epidemic. At present, it is not clear what arm of the immune response correlates with protection from HIV-1 infection or disease. Therefore, a strong cellular and humoral immune response will likely be needed to control this infection. Among different vaccine alternatives, DNA vaccines appeared more than a decade ago, demonstrating important qualities of inducing both humoral and cellular immune responses in animal models. However, after several years and various clinical studies in humans, supporting the safety of the HIV-DNA vaccine strategies, it has become clear that their potency should be improved. One way to modulate and enhance the immune responses induced by a DNA vaccine is by including genetic adjuvants such as cytokines, chemokines, or T-cell costimulatory molecules as part of the vaccine itself. Particularly, vaccine immunogenicity can be modulated by factors that attract professional antigen-presenting cells, provide additional costimulation, or enhance the uptake of plasmid DNA. This review focuses on developments in the coadministration of molecular adjuvants for the enhancement of HIV-1 DNA-vaccine potency.

  14. Selective use of adjuvant radiation therapy in resectable colorectal adenocarcinoma

    International Nuclear Information System (INIS)

    Cohen, A.M.; Gunderson, L.L.; Welch, C.E.

    1981-01-01

    Colorectal cancer recurs within the operative field in 10-20 per cent of patients undergoing potentially curative surgery. In certain subgroups, the recurrence rate is 20-50 per cent. There are some data to suggest either preoperative or postoperative radiation therapy as an adjuvant to potentially curative surgery can reduce the local operative failure rate. However, since radiation therapy has significant side effects, patient selection to maximize the therapeutic ratio is important. This report defines the criteria at the Massachusetts General Hospital for selection of patients with colorectal cancer for adjuvant radiation therapy, defines radiation therapy-surgery sequencing alternatives used, and describes techniques to reduce radiation side effects. Over a period of three and a half years, 196 patients received adjuvant radiation therapy: 51 patients received either moderate or low dose preoperative radiation therapy to rectal or rectosigmoid cancers, and 161 patients received postoperative radiation therapy to the pelvis or extrapelvic colonic tumor-lymph node beds. Some patients who received low-dose preoperative radiation therapy also received moderate-dose postoperative radiation therapy. We prefer moderate-dose postoperative radiation therapy as the approach most likely to decrease the local recurrence rate with minimal interference with surgical procedures and late small-bowel complications. Patients who received postoperative radiation therapy were those without distant metastases, whose primary tumor pathology revealed macroscopic or extensive microscopic transmural tumor penetration into extraperitoneal tissues. Careful case selection, multiple field techniques, the use of reperitonealization, omental flaps, and retroversion of the uterus into the pelvis were combined with postoperative small-bowel x-rays, bladder distention, and lateral portals to minimize radiation damage to normal structures

  15. Adjuvant Ab Interno Tumor Treatment After Proton Beam Irradiation.

    Science.gov (United States)

    Seibel, Ira; Riechardt, Aline I; Heufelder, Jens; Cordini, Dino; Joussen, Antonia M

    2017-06-01

    This study was performed to show long-term outcomes concerning globe preservation in uveal melanoma patients after proton beam therapy with the main focus on outcomes according to different adjuvant ab interno surgical procedures. Retrospective cohort study. All patients treated with primary proton beam therapy for choroidal or ciliary body melanoma between June 1998 and June 2015 were included. A total of 2499 patients underwent primary proton beam therapy, with local tumor control and globe preservation rates of 95.9% and 94.8% after 5 years, respectively. A total of 110 (4.4%) patients required secondary enucleation. Unresponsive neovascular glaucoma was the leading cause of secondary enucleation in 78 of the 2499 patients (3.1%). The 5-year enucleation-free survival rate was 94.8% in the endoresection group, 94.3% in the endodrainage group, and 93.5% in the comparator group. The log-rank test showed P = .014 (comparator group vs endoresection group) and P = .06 (comparator group vs endodrainage-vitrectomy group). Patients treated with endoresection or endodrainage-vitrectomy developed less radiation retinopathy (30.5% and 37.4% after 5 years, P = .001 and P = .048 [Kaplan-Meier], respectively) and less neovascular glaucoma (11.6% and 21.3% after 5 years, P = .001 and P = .01 [Kaplan-Meier], respectively) compared with the comparator group (52.3% radiation retinopathy and 57.8% neovascular glaucoma after 5 years). This study suggests that in larger tumors the enucleation and neovascular glaucoma rates might be reduced by adjuvant surgical procedures. Although endoresection is the most promising adjuvant treatment option, the endodrainage-vitrectomy is recommended in patients who are ineligible for endoresection. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Melanoma Metastases to the Neck Nodes: Role of Adjuvant Irradiation

    International Nuclear Information System (INIS)

    Strojan, Primoz; Jancar, Boris; Cemazar, Maja; Perme, Maja Pohar; Hocevar, Marko

    2010-01-01

    Purpose: To review experiences in the treatment of regionally advanced melanoma to the neck and/or parotid with emphasis on the role of adjuvant radiotherapy. Patients and Methods: Clinical and histopathologic data, treatment details, and outcomes in patients treated during the period 2000-2006 at the Institute of Oncology, Ljubljana, Slovenia, were reviewed. Results: A total of 40 patients with 42 dissections underwent surgery, and 43 patients with 45 dissections received irradiation postoperatively to a median equivalent dose (eqTD 2 : 2 Gy/fraction, 1 fraction/day, 5 fractions/week) of 60 Gy (range, 47.8-78.8). Regional control 2 years after surgery was 56% (95% confidence interval [CI] 40-72%) and after postoperative radiotherapy 78% (CI 63-92%) (p = 0.015). On multivariate analysis, postoperative radiotherapy (yes vs. no: hazard ratio [HR] 6.3, CI 2.0-20.6) and sum of the risk factors present (i.e., risk factor score; HR 1.7 per score point, CI 1.2-2.6) were predictive for regional control. On logistic regression testing, the number of involved nodes was associated with the probability of distant metastases (p = 0.021). The incidence of late toxicity did not correlate with the mode of therapy, eqTD 2 , or fractionation pattern. Conclusions: Adjuvant radiotherapy has the potential to compensate effectively for the negative impact of adverse histopatologic features to disease control in a dissected nodal basin. More conventionally fractionated radiotherapy regimens using fraction doses of 2-2.5 Gy, with cumulative eqTD 2 ≥60 Gy, are recommended. The number of involved lymph nodes is proposed as an additional criterion for limiting the implementation of adjuvant irradiation.

  17. Adjuvant radiotherapy with brachytherapy boost in soft tissue sarcomas

    Directory of Open Access Journals (Sweden)

    Annalisa Cortesi

    2017-06-01

    Full Text Available Purpose: The standard primary treatment for soft tissue sarcoma (STS is a wide surgical resection, preceded or followed by radiotherapy. Purpose of this retrospective study was to assess the efficacy of perioperative brachytherapy (BRT plus postoperative external beam radiation therapy (EBRT in patients with intermediate-high risk STS. Material and methods : BRT delivered dose was 20 Gy. External beam radiation therapy was delivered with 3D-technique using multiple beams. The prescribed dose was 46 Gy to the PTV. Neoadjuvant and adjuvant chemotherapy (CHT was used in patients with potentially chemosensitive histological subtypes. The primary aim of the study was to analyze overall survival (OS and local control (LC in a large patient population treated with surgery, perioperative BRT, and adjuvant EBRT ± CHT. Secondary objective was to identify prognostic factors for patients outcome in terms of LC, disease-free survival (DFS, and OS. Results : From 2000 to 2011, 107 patients presenting 2-3 grade (FNLCC primary or recurrent STS were treated with surgery, perioperative BRT, and adjuvant EBRT ± CHT. Five-year LC and OS were 80.9% and 87.4%, respectively. At univariate analysis, a higher LC was recorded in primary vs. recurrent tumors (p = 0.015, and in lower limb tumors vs. other sites (p = 0.027. An improved DFS was recorded in patients with lower limb tumors vs. other sites (p = 0.034. Conclusions : The combination of BRT and EBRT was able to achieve satisfactory results even in a patients population with intermediate-high risk STS. Patients with recurrent or other than lower limb sited tumors show a worse LC.

  18. Adjuvant radiotherapy with brachytherapy boost in soft tissue sarcomas

    Science.gov (United States)

    Cortesi, Annalisa; Galuppi, Andrea; Arcelli, Alessandra; Romani, Fabrizio; Mattiucci, Gian Carlo; Bianchi, Giuseppe; Ferrari, Stefano; Ferraro, Andrea; Farioli, Andrea; Gambarotti, Marco; Righi, Alberto; Macchia, Gabriella; Deodato, Francesco; Cilla, Savino; Buwenge, Milly; Valentini, Vincenzo; Morganti, Alessio Giuseppe; Donati, Davide; Cammelli, Silvia

    2017-01-01

    Purpose The standard primary treatment for soft tissue sarcoma (STS) is a wide surgical resection, preceded or followed by radiotherapy. Purpose of this retrospective study was to assess the efficacy of perioperative brachytherapy (BRT) plus postoperative external beam radiation therapy (EBRT) in patients with intermediate-high risk STS. Material and methods BRT delivered dose was 20 Gy. External beam radiation therapy was delivered with 3D-technique using multiple beams. The prescribed dose was 46 Gy to the PTV. Neoadjuvant and adjuvant chemotherapy (CHT) was used in patients with potentially chemosensitive histological subtypes. The primary aim of the study was to analyze overall survival (OS) and local control (LC) in a large patient population treated with surgery, perioperative BRT, and adjuvant EBRT ± CHT. Secondary objective was to identify prognostic factors for patients outcome in terms of LC, disease-free survival (DFS), and OS. Results From 2000 to 2011, 107 patients presenting 2-3 grade (FNLCC) primary or recurrent STS were treated with surgery, perioperative BRT, and adjuvant EBRT ± CHT. Five-year LC and OS were 80.9% and 87.4%, respectively. At univariate analysis, a higher LC was recorded in primary vs. recurrent tumors (p = 0.015), and in lower limb tumors vs. other sites (p = 0.027). An improved DFS was recorded in patients with lower limb tumors vs. other sites (p = 0.034). Conclusions The combination of BRT and EBRT was able to achieve satisfactory results even in a patients population with intermediate-high risk STS. Patients with recurrent or other than lower limb sited tumors show a worse LC. PMID:28725250

  19. Adjuvant radiotherapy for cutaneous melanoma: Comparing hypofractionation to conventional fractionation

    International Nuclear Information System (INIS)

    Chang, Daniel T.; Amdur, Robert J.; Morris, Christopher G. M.S.; Mendenhall, William M.

    2006-01-01

    Purpose: To examine locoregional control after adjuvant radiotherapy (RT) for cutaneous melanoma and compare outcomes between conventional fractionation and hypofractionation. Methods and Materials: Between January 1980 and June 2004, 56 patients with high-risk disease were treated with adjuvant RT. Indications for RT included: recurrent disease, cervical lymph node involvement, lymph nodes >3 cm, more than three lymph nodes involved, extracapsular extension, gross residual disease, close or positive margins, or satellitosis. Hypofractionation was used in 41 patients (73%) and conventional fractionation was used in 15 patients (27%). Results: The median age was 61 years (21->90). The median follow-up among living patients was 4.4 years (range, 0.6-14.4 years). The primary site was located in the head and neck in 49 patients (87%) and below the clavicles in 7 patients (13%). There were 7 in-field locoregional failures (12%), 3 out-of-field regional failures (5%), and 24 (43%) distant failures. The 5-year in-field locoregional control (ifLRC) and freedom from distant metastases (FFDM) rates were 87% and 43%, respectively. The 5-year cause-specific (CSS) and overall survival (OS) was 57% and 46%, respectively. The only factor associated with ifLRC was satellitosis (p = 0.0002). Nodal involvement was the only factor associated with FFDM (p = 0.0007), CSS (p = 0.0065), and OS (p = 0.016). Two patients (4%) who experienced severe late complications, osteoradionecrosis of the temporal bone and radiation plexopathy, and both received hypofractionation (5%). Conclusions: Although surgery and adjuvant RT provides excellent locoregional control, distant metastases remain the major cause of mortality. Hypofractionation and conventional fractionation are equally efficacious

  20. Adjuvant Treatment after Surgery in Stage IIIA Endometrial Adenocarcinoma

    Science.gov (United States)

    Yoon, Mee Sun; Huh, Seung Jae; Kim, Hak Jae; Kim, Young Seok; Kim, Yong Bae; Kim, Joo-Young; Lee, Jong-Hoon; Kim, Hun Jung; Cha, Jihye; Kim, Jin Hee; Kim, Juree; Yoon, Won Sup; Choi, Jin Hwa; Chun, Mison; Choi, Youngmin; Lee, Kang Kyoo; Kim, Myungsoo; Jeong, Jae-Uk; Chang, Sei Kyung; Park, Won

    2016-01-01

    Purpose We evaluated the role of adjuvant therapy in stage IIIA endometrioid adenocarcinoma patients who underwent surgery followed by radiotherapy (RT) alone or chemoradiotherapy (CTRT) according to risk group. Materials and Methods A multicenter retrospective study was conducted including patients with surgical stage IIIA endometrial cancertreated by radical surgery and adjuvant RT or CTRT. Disease-free survival (DFS) and overall survival (OS) were analyzed. Results Ninety-three patients with stage IIIA disease were identified. Nineteen patients (20.4%) experienced recurrence, mostly distant metastasis (17.2%). Combined CTRT did not affect DFS (74.1% vs. 82.4%, p=0.130) or OS (96.3% vs. 91.9%, p=0.262) in stage IIIA disease compared with RT alone. Patients with age ≥ 60 years, grade G2/3, and lymphovascular space involvement had a significantly worse DFS and those variables were defined as risk factors. The high-risk group showed a significant reduction in 5-year DFS (≥ 2 risk factors) (49.0% vs. 88.0%, p < 0.001) compared with the low-risk group (< 2). Multivariate analysis confirmed that more than one risk factor was the only predictor of worse DFS (hazard ratio, 5.45; 95% confidence interval, 2.12 to 13.98; p < 0.001). Of patients with no risk factors, a subset treated with RT alone showed an excellent 5-year DFS and OS (93.8% and 100%, respectively). Conclusion We identified a low-risk subset of stage IIIA endometrioid adenocarcinoma patients who might be reasonable candidates for adjuvant RT alone. Further randomized studies are needed to determine which subset might benefit from combined CTRT. PMID:26511800

  1. Cyclic GMP-AMP Displays Mucosal Adjuvant Activity in Mice

    OpenAIRE

    Škrnjug, Ivana; Guzmán, Carlos Alberto; Ruecker, Christine

    2014-01-01

    The recently discovered mammalian enzyme cyclic GMP-AMP synthase produces cyclic GMP-AMP (cGAMP) after being activated by pathogen-derived cytosolic double stranded DNA. The product can stimulate STING-dependent interferon type I signaling. Here, we explore the efficacy of cGAMP as a mucosal adjuvant in mice. We show that cGAMP can enhance the adaptive immune response to the model antigen ovalbumin. It promotes antigen specific IgG and a balanced Th1/Th2 lymphocyte response in immunized mice....

  2. Postoperative adjuvant therapy of breast cancer. Oncology Overview

    International Nuclear Information System (INIS)

    1984-12-01

    Oncology Overviews are a service of the International Cancer Research Data Bank (ICRDB) Program of the National Cancer Institute, intended to facilitate and promote the exchange of information between cancer scientists by keeping them aware of literature related to their research being published by other laboratories throughout the world. Each Oncology Overview represents a survey of the literature associated with a selected area of cancer research. It contains abstracts of articles which have been selected and organized by researchers associated with the field. Contents: Postoperative chemotherapy; Postoperative radiotherapy; Postoperative hormone therapy; Postoperative immunotherapy and chemoimmunotherapy; Postoperative multimodal therapy; Prognostic factors in postoperative adjuvant therapy

  3. Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Morris, M M; Dallow, K C; Zietman, A L; Althausen, A F; Heney, N M; McGovern, F J; Shipley, W U

    1995-07-01

    Purpose: To assess the ability of adjuvant irradiation to prevent PSA failure in cases of pT3N0 disease, and of salvage irradiation to durably suppress a rising PSA following radical prostatectomy. Methods and Materials: 62 patients treated by post-operative radiation therapy (60-64Gy in 1.8Gy fractions to the tumor bed) between 1988 and 1993 were evaluated. All had complete pre- and post-radiation PSA data. Median follow up was 3.2 years from time of surgery and 2.2 years from irradiation. 20 patients had Gleason grade 3 disease (moderately differentiated) and 41 Gleason 4-5 (poorly differentiated). 46 had positive inked surgical margins, 18 involved seminal vesicles and 5 had palpable recurrent disease. None had known nodal or metastatic disease. 32 patients underwent adjuvant treatment (undetectable PSA at time of irradiation) and 30 salvage (detectable PSA at time of irradiation). Kaplan-Meier life table analysis was employed. The endpoint studied was freedom from biochemical failure. This was defined as a rise in the PSA of greater than 10% (intra laboratory error <8%) or a previously undetectable PSA becoming detectable. Results: The overall actuarial freedom from biochemical failure at 4 years from radiotherapy was 59%. A significant difference was seen between those receiving adjuvant and those receiving salvage irradiation (71% vs 51%, p=0.03). Amongst those in the salvage group neither the PSA prior to surgery, the PSA at the time of irradiation, the seminal vesicle status, nor the Gleason score (3 vs 4-5) correlated significantly with outcome. The time interval between surgery and irradiation was, however, significant. Those being treated within 6 months fared better than those treated later (60% vs 36%, p=0.04). Further, those treated early were more likely to achieve an undetectable nadir PSA level (94% vs 71%). Conclusion: The addition of adjuvant irradiation appears to improve the 4 year biochemical disease-free survival of patients with poor

  4. Adjuvant chemo-radiation for gastric adenocarcinoma: an institutional experience

    International Nuclear Information System (INIS)

    Aftimos, Philippe G; Nasr, Elie A; Nasr, Dolly I; Noun, Roger J; Nasr, Fady L; Ghosn, Marwan G; El Helou, Joelle A; Chahine, Georges Y

    2010-01-01

    Studies have shown that surgery alone is less than satisfactory in the management of early gastric cancer, with cure rates approaching 40%. The role of adjuvant therapy was indefinite until three large, randomized controlled trials showed the survival benefit of adjuvant therapy over surgery alone. Chemoradiation therapy has been criticized for its high toxicity. 24 patients diagnosed between September 2001 and July 2007 were treated with adjuvant chemoradiation. 18 patients had the classical MacDonald regimen of 4500 cGy of XRT and chemotherapy with 5-fluorouracil (5FU) and leucovorin, while chemotherapy consisted of 5FU/Cisplatin for 6 patients. This series consisted of non-metastatic patients, 17 females and 7 males with a median age of 62.5 years. 23 patients (96%) had a performance status of 0 or 1. The full course of radiation therapy (4500 cGy) was completed by 22 patients (91.7%). Only 7 patients (36.8%) completed the total planned courses of chemotherapy. 2 local relapses (10%), 2 regional relapses (10%) and 2 distant relapses (10%) were recorded. Time to progression has not been reached. 9 patients (37.5%) died during follow-up with a median overall survival of 75 months. Patients lost a mean of 4 Kgs during radiation therapy. We recorded 6 episodes of febrile neutropenia and the most frequent toxicity was gastro-intestinal in 17 patients (70.8%) with 9 (36%) patients suffering grade 3 or 4 toxicity and 5 patients (20%) suffering from grade 3 or 4 neutropenia. 4 (17%) patients required total parenteral nutrition for a mean duration of 20 days. 4 patients suffered septic shock (17%) and 1 patient developed a deep venous thrombosis and a pulmonary embolus. Adjuvant chemo-radiation for gastric cancer is a standard at our institution and has resulted in few relapses and an interesting median survival. Toxicity rates were serious and this remains a harsh regimen with only 36.8% of patients completing the full planned courses of chemotherapy. This is due to

  5. Adjuvant chemo-radiation for gastric adenocarcinoma: an institutional experience

    Directory of Open Access Journals (Sweden)

    Ghosn Marwan G

    2010-06-01

    Full Text Available Abstract Background Studies have shown that surgery alone is less than satisfactory in the management of early gastric cancer, with cure rates approaching 40%. The role of adjuvant therapy was indefinite until three large, randomized controlled trials showed the survival benefit of adjuvant therapy over surgery alone. Chemoradiation therapy has been criticized for its high toxicity. Methods 24 patients diagnosed between September 2001 and July 2007 were treated with adjuvant chemoradiation. 18 patients had the classical MacDonald regimen of 4500 cGy of XRT and chemotherapy with 5-fluorouracil (5FU and leucovorin, while chemotherapy consisted of 5FU/Cisplatin for 6 patients. Results This series consisted of non-metastatic patients, 17 females and 7 males with a median age of 62.5 years. 23 patients (96% had a performance status of 0 or 1. The full course of radiation therapy (4500 cGy was completed by 22 patients (91.7%. Only 7 patients (36.8% completed the total planned courses of chemotherapy. 2 local relapses (10%, 2 regional relapses (10% and 2 distant relapses (10% were recorded. Time to progression has not been reached. 9 patients (37.5% died during follow-up with a median overall survival of 75 months. Patients lost a mean of 4 Kgs during radiation therapy. We recorded 6 episodes of febrile neutropenia and the most frequent toxicity was gastro-intestinal in 17 patients (70.8% with 9 (36% patients suffering grade 3 or 4 toxicity and 5 patients (20% suffering from grade 3 or 4 neutropenia. 4 (17% patients required total parenteral nutrition for a mean duration of 20 days. 4 patients suffered septic shock (17% and 1 patient developed a deep venous thrombosis and a pulmonary embolus. Conclusions Adjuvant chemo-radiation for gastric cancer is a standard at our institution and has resulted in few relapses and an interesting median survival. Toxicity rates were serious and this remains a harsh regimen with only 36.8% of patients completing the

  6. Adjuvant activity of ambient particulate matter of different sites, sizes, and seasons in a respiratory allergy mouse model

    International Nuclear Information System (INIS)

    Steerenberg, P.A.; Withagen, C.E.T.; Dalen, W.J. van; Dormans, J.A.M.A.; Cassee, F.R.; Heisterkamp, S.H.; Loveren, H. van

    2004-01-01

    In the framework of an EU project entitled, 'Respiratory Allergy and Inflammation due to Ambient Particles (RAIAP)', various ambient particulate matter samples were tested for their adjuvant potency in an animal allergy model to ovalbumin. Coarse (2.5-10 μm) and fine (0.15-2.5 μm) particles were collected during the spring, summer, and winter in Rome, Oslo, Lodz, and Amsterdam. Coarse and fine particles were also collected near a seaside location in the Netherlands, where prevailing winds are westerly. These latter particles served as a control, with a minimum contribution by traffic. Ottawa dust (EHC-93) was used as a standard reference sample. Immunoglobulins (IgE, IgG 1 , and IgG 2a ), histopathological changes in the lung, cytokines, and the number of cells and their differentiation in lung lavages were used as effect parameters to study the adjuvant potency of these particles. The particles (3 mg/ml) were mixed with ovalbumin (0.4 mg/ml) and intranasally administered during the sensitization or the challenge phase. Intranasal administration of ovalbumin only induced very little antibody response, but introduced a minor inflammatory response in the lung or BAL during the sensitization and challenge phase. On the contrary, after coexposure to EHC-93 and ovalbumin, a major increase was found in immunoglobulin levels specific for ovalbumin, and a major inflammatory response in lung and BAL was induced. Coexposure to ovalbumin with 4 out of 12 collected PM samples (3 mg/ml) resulted in an increase of mainly IgE and IgG 1 . The histopathological changes consisted of a small to severe peribronchial and perivascular inflammatory response, a hypertrophy of bronchiolar mucous cells and an increase in eosinophils and neutrophils in the BAL. Statistical evaluation of the above-mentioned parameters showed associations with PM x (coarse and fine), site, season, season x PM x , season x site and PM x x site. In addition, adjuvant activity of the PM x can be ranked as Lodz

  7. Development of Novel Protocol for Preclinical Monitoring the Release of Adjuvants Encapsulated Mucosal Delivery Carriers

    Directory of Open Access Journals (Sweden)

    Mohamed Ibrahim-Saeed

    2015-12-01

    Full Text Available This work contributes in vaccines down-stream process by introducing a novel platform for in-vitro monitoring of vaccine-adjuvant delivery profile as a crucial preclinical optimizing step in mucosal vaccines. Nano and micro particles of Calcium phosphate (Cap vaccine-adjuvant were encapsulated in Chitosan and Alginate polymeric carriers. Adjuvants release profiles monitored in a permeable bag at 37°C, pH 2, incubated in isotonic buffer for 96 hours. The released Calcium in the outer buffer was monitored and compared in-addition to the carrier’s swelling and biophysical properties. The adjuvants and carriers did not interfere with the proliferation of cultured hepatocytes an indicator of their safe use; Chitosan’s viscosity and swelling were higher than Alginate. Chitosan’s Zeta-potential was significantly high positive, while Cap and Alginate were negative. The prepared CaP and Chitosan particles were in nano-size, while the ready-made CaP adjuvant and Alginate were in micro-size using zeta-seizer and scanning electron-micrograph. The release of nano-size particle was in ascending, extended and controlled manner compared to micro-size adjuvant. Moreover, nano-adjuvant release profile from Chitosan was superior compared to Alginate. The core controlling factors in vaccine-adjuvant sustained release includes; smaller adjuvant particles (nano-size, carrier’s low swelling, high viscosity and importantly carrier-adjuvant entrapment reversibility. Chitosan offers sustained ascending superior capacity in releasing Nano-Cap adjuvant. This novel in-vitro pre-clinical study answer a crucial downstream preparative step for optimizing mucosal vaccines before their direct routine in-vivo trial on animal regardless of adjuvant’s particle size or delivery kinetics.

  8. Who Benefits From Adjuvant Radiation Therapy for Gastric Cancer? A Meta-Analysis

    International Nuclear Information System (INIS)

    Ohri, Nitin; Garg, Madhur K.; Aparo, Santiago; Kaubisch, Andreas; Tome, Wolfgang; Kennedy, Timothy J.; Kalnicki, Shalom; Guha, Chandan

    2013-01-01

    Purpose: Large randomized trials have demonstrated significant survival benefits with the use of adjuvant chemotherapy or chemoradiation therapy for gastric cancer. The importance of adjuvant radiation therapy (RT) remains unclear. We performed an up-to-date meta-analysis of randomized trials testing the use of RT for resectable gastric cancer. Methods and Materials: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials testing adjuvant (including neoadjuvant) RT for resectable gastric cancer. Hazard ratios describing the impact of adjuvant RT on overall survival (OS) and disease-free survival (DFS) were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. Subgroup analyses were performed to determine whether the efficacy of RT varies with chemotherapy use, RT timing, geographic region, type of nodal dissection performed, or lymph node status. Results: Thirteen studies met all inclusion criteria and were used for this analysis. Adjuvant RT was associated with a significant improvement in both OS (HR = 0.78, 95% CI: 0.70-0.86, P<.001) and DFS (HR = 0.71, 95% CI: 0.63-0.80, P<.001). In the 5 studies that tested adjuvant chemoradiation therapy against adjuvant chemotherapy, similar effects were seen for OS (HR = 0.83, 95% CI: 0.67-1.03, P=.087) and DFS (HR = 0.77, 95% CI: 0.91-0.65, P=.002). Available data did not reveal any subgroup of patients that does not benefit from adjuvant RT. Conclusion: In randomized trials for resectable gastric cancer, adjuvant RT provides an approximately 20% improvement in both DFS and OS. Available data do not reveal a subgroup of patients that does not benefit from adjuvant RT. Further study is required to optimize the implementation of adjuvant RT for gastric cancer with regard to patient selection and integration with systemic therapy

  9. Use of the Microparticle Nanoscale Silicon Dioxide as an Adjuvant To Boost Vaccine Immune Responses against Influenza Virus in Neonatal Mice.

    Science.gov (United States)

    Russell, Ryan F; McDonald, Jacqueline U; Lambert, Laura; Tregoning, John S

    2016-05-01

    Neonates are at a high risk of infection, but vaccines are less effective in this age group; tailored adjuvants could potentially improve vaccine efficacy. Increased understanding about danger sensing by the innate immune system has led to the rational design of novel adjuvants. But differences in the neonatal innate immune response, for example, to Toll-like receptor (TLR) agonists, can reduce the efficacy of these adjuvants in early life. We therefore targeted alternative danger-sensing pathways, focusing on a range of compounds described as inflammasome agonists, including nanoscale silicon dioxide (NanoSiO2), calcium pyrophosphate dihydrate (CPPD) crystals, and muramyl tripeptide (M-Tri-DAP), for their ability to act as adjuvants.In vitro, these compounds induced an interleukin 1-beta (IL-1β) response in the macrophage-like cell line THP1.In vivo, adult CB6F1 female mice were immunized intramuscularly with H1N1 influenza vaccine antigens in combination with NanoSiO2, CPPD, or M-Tri-DAP and subsequently challenged with H1N1 influenza virus (A/England/195/2009). The adjuvants boosted anti-hemagglutinin IgG and IgA antibody levels. Both adult and neonatal animals that received NanoSiO2-adjuvanted vaccines lost significantly less weight and recovered earlier after infection than control animals treated with antigen alone. Administration of the adjuvants led to an influx of activated inflammatory cells into the muscle but to little systemic inflammation measured by serum cytokine levels. Blocking IL-1β or caspase 1 in vivo had little effect on NanoSiO2 adjuvant function, suggesting that it may work through pathways other than the inflammasome. Here we demonstrate that NanoSiO2 can act as an adjuvant and is effective in early life. Vaccines can fail to protect the most at-risk populations, including the very young, the elderly, and the immunocompromised. There is a gap in neonatal immunity between the waning of maternal protection and routine infant immunization

  10. Th1 immune response to Plasmodium falciparum recombinant thrombospondin-related adhesive protein (TRAP) antigen is enhanced by TLR3-specific adjuvant, poly(I:C) in BALB/c mice.

    Science.gov (United States)

    Mehrizi, A A; Ameri Torzani, M; Zakeri, S; Jafary Zadeh, A; Babaeekhou, L

    2018-07-01

    Sporozoite-based malaria vaccines have provided a gold standard for malaria vaccine development, and thrombospondin-related adhesive protein (TRAP) serves as the main vaccine candidate antigen on sporozoites. As recombinant malaria vaccine candidate antigens are poorly immunogenic, additional appropriate immunostimulants, such as an efficient adjuvant, are highly essential to modulate Th1-cell predominance and also to induce a protective and long-lived immune response. In this study, polyinosinic:polycytidylic acid [poly(I:C)], the ligand of TLR3, was considered as the potential adjuvant for vaccines targeting stronger Th1-based immune responses. For this purpose, BALB/c mice were immunized with rPfTRAP delivered in putative poly(I:C) adjuvant, and humoural and cellular immune responses were determined in different immunized mouse groups. Delivery of rPfTRAP with poly(I:C) induced high levels and titres of persisted and also high-avidity anti-rPfTRAP IgG antibodies comparable to complete Freund's adjuvant (CFA)/incomplete Freund's adjuvant (IFA) adjuvant after the second boost. In addition, rPfTRAP formulated with poly(I:C) elicited a higher ratio of IFN-γ/IL-5, IgG2a/IgG1, and IgG2b/IgG1 than with CFA/IFA, indicating that poly(I:C) supports the induction of a stronger Th1-based immune response. This is a first time study which reveals the potential of rPfTRAP delivery in poly(I:C) to increase the level, avidity and durability of both anti-PfTRAP cytophilic antibodies and Th1 cytokines. © 2018 John Wiley & Sons Ltd.

  11. Intranasal immunization with fusion protein MrpH·FimH and MPL adjuvant confers protection against urinary tract infections caused by uropathogenic Escherichia coli and Proteus mirabilis.

    Science.gov (United States)

    Habibi, Mehri; Asadi Karam, Mohammad Reza; Shokrgozar, Mohammad Ali; Oloomi, Mana; Jafari, Anis; Bouzari, Saeid

    2015-04-01

    Urinary tract infections (UTIs) caused by Uropathogenic Escherichia coli (UPEC) and Proteus mirabilis are among the most common infections in the world. Currently there are no vaccines available to confer protection against UTI in humans. In this study, the immune responses and protection of FimH of UPEC with MrpH antigen of P. mirabilis in different vaccine formulations with and without MPL adjuvant were assessed. Mice intranasally immunized with the novel fusion protein MrpH·FimH induced a significant increase in IgG and IgA in serum, nasal wash, vaginal wash, and urine samples. Mice immunized with fusion MrpH·FimH also showed a significant boost in cellular immunity. Addition of MPL as the adjuvant enhanced FimH and MrpH specific humoral and cellular responses in both systemic and mucosal samples. Vaccination with MrpH·FimH alone or in combination with MPL showed the highest efficiency in clearing bladder and kidney infections in mice challenged with UPEC and P. mirabilis. These findings may indicate that the protection observed correlates with the systemic, mucosal and cellular immune responses induced by vaccination with these preparations. Our data suggest MrpH·FimH fusion protein with or without MPL as adjuvant could be potential vaccine candidates for elimination of UPEC and P. mirabilis. These data altogether are promising and these formulations are good candidates for elimination of UPEC and P. mirabilis. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. IL-27p28 Production by XCR1+ Dendritic Cells and Monocytes Effectively Predicts Adjuvant-Elicited CD8+ T Cell Responses.

    Science.gov (United States)

    Kilgore, Augustus M; Welsh, Seth; Cheney, Elizabeth E; Chitrakar, Alisha; Blain, Trevor J; Kedl, Benjamin J; Hunter, Chris A; Pennock, Nathan D; Kedl, Ross M

    2018-01-01

    It is well accepted that the innate response is a necessary prerequisite to the formation of the adaptive response. This is true for T cell responses against infections or adjuvanted subunit vaccination. However, specific innate parameters with predictive value for the magnitude of an adjuvant-elicited T cell response have yet to be identified. We previously reported how T cell responses induced by subunit vaccination were dependent on the cytokine IL-27. These findings were unexpected, given that T cell responses to an infection typically increase in the absence of IL-27. Using a novel IL-27p28-eGFP reporter mouse, we now show that the degree to which an adjuvant induces IL-27p28 production from dendritic cells and monocytes directly predicts the magnitude of the T cell response elicited. To our knowledge, these data are the first to identify a concrete innate correlate of vaccine-elicited cellular immunity, and they have significant practical and mechanistic implications for subunit vaccine biology.

  13. Adjuvant activity of peptidoglycan monomer and its metabolic products.

    Science.gov (United States)

    Halassy, Beata; Krstanović, Marina; Frkanec, Ruza; Tomasić, Jelka

    2003-02-14

    Peptidoglycan monomer (PGM) is a natural compound of bacterial origin. It is a non-toxic, non-pyrogenic, water-soluble immunostimulator potentiating humoral immune response to ovalbumin (OVA) in mice. It is fast degraded and its metabolic products-the pentapeptide (PP) and the disaccharide (DS)-are excreted from the mammalian organism upon parenteral administration. The present study investigates: (a). whether PGM could influence the long-living memory generation; (b). whether metabolic products retain adjuvant properties of the parent compound and contribute to its adjuvanticity. We report now that mice immunised twice with OVA+PGM had significantly higher anti-OVA IgG levels upon challenge with antigen alone 6 months later in comparison to control group immunised with OVA only. PP and DS were prepared enzymatically in vitro as apyrogenic and chemically pure compounds. When mice were immunised with OVA plus PP and DS, respectively, the level of anti-OVA IgGs in sera was not higher than in mice immunised with OVA alone, while PGM raised the level of specific antibodies. Results implicate that the adjuvant active molecule, capable of enhancing long-living memory generation, is PGM itself, and none of its metabolic products.

  14. Preparation and evaluation of functional foods in adjuvant arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Al-Okbi, S. Y.; Mohamed, D. A.

    2012-07-01

    Adjuvant arthritis is an animal model that closely resembles rheumatoid arthritis in humans. It is a successful working model used to study new anti-inflammatory agents. In previous studies (animal and clinical) we have shown that evening primrose oil, fish oil and the methanol extract of date fruits and fenugreek seeds have anti-inflammatory activity and that the methanol extract of dates has an antioxidant effect. Based on these studies, the aim of the present study was to prepare 7 functional foods containing such bioactive fractions separately or in combination and to evaluate them in adjuvant arthritis in rats, study the stability of bioactive ingredients and evaluate their sensory properties. The studied biochemical parameters were erythrocyte sedimentation rate, erythrocyte superoxide dismutase, glutathione peroxidase and plasma copper, zinc and interlukin 2. Nutritional parameters, including body weight gain, food intake and food efficiency ratio were monitored during the feeding of the functional foods. The bioactive ingredients assessed were total phenolic contents and fatty acids. The results showed improvement in the biochemical parameters, body weight gain and food efficiency ratio of arthritic rats fed on the functional foods with different degrees. All the prepared functional foods were sensory accepted. The active ingredients showed stability during storage. In conclusion, all the tested functional foods showed promising antiinflammatory activity and were determined to be acceptable through sensory evaluation which means that their potential beneficial use as dietary supplements in rheumatoid arthritis patients may be recommended. (Author) 42 refs.

  15. [Environmental pollutants as adjuvant factors of immune system derived diseases].

    Science.gov (United States)

    Lehmann, Irina

    2017-06-01

    The main task of the immune system is to protect the body against invading pathogens. To be able to do so, immune cells must be able to recognize and combat exogenous challenges and at the same time tolerate body-borne structures. A complex regulatory network controls the sensitive balance between defense and tolerance. Perturbation of this network ultimately leads to the development of chronic inflammation, such as allergies, autoimmune reactions, and infections, because the immune system is no longer able to efficiently eliminate invading pathogens. Environmental pollutants can cause such perturbations by affecting the function of immune cells in such a way that they would react hypersensitively against allergens and the body's own structures, respectively, or that they would be no longer able to adequately combat pathogens. This indirect effect is also known as adjuvant effect. For pesticides, heavy metals, wood preservatives, or volatile organic compounds such adjuvant effects are well known. Examples of the mechanism by which environmental toxins contribute to chronic inflammatory diseases are manifold and will be discussed along asthma and allergies.While the immune system of healthy adults is typically well able to distinguish between foreign and endogenous substances even under adverse environmental conditions, that of children would react much more sensible upon comparable environmental challenges. To prevent priming for diseases by environmental cues during that highly sensitive period of early childhood children are to be particularly protected.

  16. Controversies in breast cancer: adjuvant and neoadjuvant therapy.

    Science.gov (United States)

    Montemurro, Filippo; Redana, Stefania; Valabrega, Giorgio; Aglietta, Massimo

    2005-06-01

    Initial randomised studies of chemotherapy and endocrine therapy showed that systemic treatments had a substantial impact on the survival of women with early breast cancer. The original assumption was that the efficacy of these treatments was limited to those patients presenting with more adverse prognostic features. Subsequently, meta-analyses of randomised trials revealed that the benefits of chemotherapy and endocrine therapy are not mutually exclusive and extend to all the prognostic subgroups. However, the absolute benefit varies according to baseline characteristics such as tumour stage and other biological factors. Over the last 10 years, considerable progress has been made with the introduction of new drugs into the adjuvant and neoadjuvant treatment of women with breast cancer. Taxanes and third-generation aromatase inhibitors are providing proof of additional benefits compared with standard reference treatments. In parallel, research on the biology of breast cancer is establishing novel prognostic and predictive factors, which may allow better treatment tailoring. Currently, however, women with early breast cancer and their doctors face the difficult task of making therapeutic decisions often based on early results from positive studies. In a disease where follow up is crucial to fully assess the benefit and long-term toxicities of an intervention, current knowledge leaves unanswered questions that generate debate and controversy. This review will summarise recent results from randomised trials of adjuvant and neoadjuvant therapy in women with early breast cancer and focus on the current controversies.

  17. Adjuvant chemotherapy followed by conformal chemoradiotherapy in gastric carcinoma

    International Nuclear Information System (INIS)

    Bouchbika, Z.; Quero, L.; Kouto, H.; Hennequin-Baruch, V.; Sergent, G.; Maylin, C.; Hennequin, C.; Gornet, J.M.; Munoz, N.; Cojean-Zelek, I.; Houdart, R.; Panis, Y.; Valleur, P.

    2008-01-01

    Purpose: Analysis of the feasibility and results of adjuvant chemotherapy followed by conformal chemoradiotherapy after surgery for gastric carcinoma. Patients and methods Twenty-six patients (R0 or R1) were treated postoperatively by three cycles of 5-fluorouracil (5-FU) and cisplatin, followed by a concomitant association of LV5FU2 chemotherapy with a conformal radiotherapy of 45 Gy. Results: The tumor was classified pT3-T4 in 77% of the patients and 92.5% had a nodal involvement (pN1: 54%; pN2: 31%). Feasibility (1) Adjuvant chemotherapy: nausea/vomiting grade II/III: 12 patients (48%); neutropenia grade III/IV: two patients; completed in all patients, except one. (2) Chemoradiotherapy: nausea/vomiting grade II/III: 10 patients; diarrhea grade II/3: two patients; oesophagitis grade II/III: two patients; myocardial infarction/pulmonary embolism: two patients. All patients except one received the planned dose of 45 Gy. Radiotherapy was interrupted in six cases, with a median duration of 14 days. Survival: with a median follow-up of 30 months, 65% of the patients were alive without disease; median survival was 32 months. Conclusion: This postoperative schedule was judged feasible. It allowed the deliverance of a more intensified chemotherapy than the classical schedule. Its clinical benefit must be evaluated in a phase III trial. (authors)

  18. Adjuvant Chemotherapy for Stage II Colon Cancer: A Clinical Dilemma.

    Science.gov (United States)

    Kannarkatt, Joseph; Joseph, Joe; Kurniali, Peter C; Al-Janadi, Anas; Hrinczenko, Borys

    2017-04-01

    The decision to treat a patient with stage II colon cancer with adjuvant chemotherapy can be challenging. Although the benefit of treatment is clear in most patients with stage III disease, the decision to provide chemotherapy after surgical resection in stage II disease must be made on an individual basis. Several trials have demonstrated the small but absolute benefits of receiving adjuvant chemotherapy for stage II colon cancer for disease-free survival and overall survival. In an attempt to better understand the role of chemotherapy, several studies were performed that identified high-risk characteristics that can be used prognostically and predictively to aid in the clinical decision making process. ASCO, the National Comprehensive Cancer Network, and the European Society of Medical Oncology have published guidelines describing these high-risk characteristics. Since then, several other molecular markers have emerged that may offer more information on a given patient's risk for recurrence. The decision to treat a patient with stage II colon cancer must be made on an individual basis, considering the risks and benefits of treatment. In this short review, we will present the available evidence and offer possible directions for future study.

  19. Pilot study of sodium phenylbutyrate as adjuvant in cyclophosphamide-resistant endemic Burkitt's lymphoma.

    Science.gov (United States)

    Phillips, John A; Griffin, Beverly E

    2007-12-01

    Burkitt's lymphoma (BL) accounts for the majority of childhood malignancies seen in sub-Saharan Africa. In Malawi, cyclophosphamide (CPM), the mainstay of treatment for endemic BL, is effective in around 50% of cases. Evidence exists in support of an association between activation of replication of Epstein-Barr virus (EBV) in the tumour and response to this chemotheraupeutic agent. Phenylbutyrate (PB), approved for treatment of inborn errors of the urea cycle with minimal toxicity in children, induces EBV replication and cell lysis in BL-derived cell cultures. It has also shown some success as adjuvant in treatment of chronic leukaemia and lymphoma. We tested in African BL patients with CPM-resistant tumours, and thus unlikely to survive, the hypothesis that PB can reverse this resistance. A study of five patients showed PB before CPM to induce shrinkage of CPM-resistant tumours in two of them. Findings suggested that for this effect PB pre-treatment should be given for a week before CPM treatment. A larger study is indicated.

  20. The type of adjuvant strongly influences the T-cell response during nanoparticle-based immunization

    Science.gov (United States)

    Knuschke, Torben; Epple, Matthias; Westendorf, Astrid M

    2014-01-01

    Potent vaccines require the ability to effectively induce immune responses. Especially for the control of infectious diseases with intracellular pathogens, like viruses or bacteria, potent T-cell responses are indispensable. Several delivery systems such as nanoparticles have been considered to boost the immunogenicity of pathogen derived peptides or subunits for the induction of potent T-cell responses. Since they can be further functionalized with immunostimulants, like Toll-like receptor (TLR) agonists, they improve the response by enhanced activation of the innate immune system. Currently, TLR agonists like unmethylated CpG oligonucleotides and the synthetic dsRNA derivate polyriboinosinic acid-polyribocytidylic acid (poly[I:C]) are widely used as vaccine adjuvants. CpG and poly(I:C) trigger different TLRs and therefore show differential signal transduction. Recently, we established biodegradable calcium phosphate (CaP) nanoparticles as potent T cell inducing vaccination vehicles. In this commentary we discuss the role of CpG and poly(I:C) for the effective induction of virus-specific T cells during immunization with CaP nanoparticles. The presented results underline the importance of the right formulation of vaccines for specific immunization purpose. PMID:23982325

  1. Characterization of Immune Responses to an Inactivated Avian Influenza Virus Vaccine Adjuvanted with Nanoparticles Containing CpG ODN.

    Science.gov (United States)

    Singh, Shirene M; Alkie, Tamiru N; Abdelaziz, Khaled Taha; Hodgins, Douglas C; Novy, Anastasia; Nagy, Éva; Sharif, Shayan

    2016-06-01

    Avian influenza virus (AIV), a mucosal pathogen, gains entry into host chickens through respiratory and gastrointestinal routes. Most commercial AIV vaccines for poultry consist of inactivated, whole virus with adjuvant, delivered by parenteral administration. Recent advances in vaccine development have led to the application of nanoparticle emulsion delivery systems, such as poly (d,l-lactic-co-glycolic acid) (PLGA) nanoparticles to enhance antigen-specific immune responses. In chickens, the Toll-like receptor 21 ligand, CpG oligodeoxynucleotides (ODNs), have been demonstrated to be immunostimulatory. The objective of this study was to compare the adjuvant potential of CpG ODN 2007 encapsulated in PLGA nanoparticles with nonencapsulated CpG ODN 2007 when combined with a formalin-inactivated H9N2 virus, through intramuscular and aerosol delivery routes. Chickens were vaccinated at days 7 and 21 posthatch for the intramuscular route and at days 7, 21, and 35 for the aerosol route. Antibody-mediated responses were evaluated weekly in sera and lacrimal secretions in specific pathogen-free chickens. The results indicate that nonencapsulated CpG ODN 2007 in inactivated AIV vaccines administered by the intramuscular route generated higher antibody responses compared to the encapsulated CpG ODN 2007 formulation by the same route. Additionally, encapsulated CpG ODN 2007 in AIV vaccines administered by the aerosol route elicited higher mucosal responses compared to nonencapsulated CpG ODN 2007. Future studies may be aimed at evaluating protective immune responses induced with PLGA encapsulation of AIV and adjuvants.

  2. Characterization of a Broadly Reactive Anti-CD40 Agonistic Monoclonal Antibody for Potential Use as an Adjuvant.

    Directory of Open Access Journals (Sweden)

    Cameron Martin

    Full Text Available Lack of safe and effective adjuvants is a major hindrance to the development of efficacious vaccines. Signaling via CD40 pathway leads to enhanced antigen processing and presentation, nitric oxide expression, pro-inflammatory cytokine expression by antigen presenting cells, and stimulation of B-cells to undergo somatic hypermutation, immunoglobulin class switching, and proliferation. Agonistic anti-CD40 antibodies have shown promising adjuvant qualities in human and mouse vaccine studies. An anti-CD40 monoclonal antibody (mAb, designated 2E4E4, was identified and shown to have strong agonistic effects on primary cells from multiple livestock species. The mAb recognize swine, bovine, caprine, and ovine CD40, and evoked 25-fold or greater proliferation of peripheral blood mononuclear cells (PBMCs from these species relative to cells incubated with an isotype control (p<0.001. In addition, the mAb induced significant nitric oxide (p<0.0001 release by bovine macrophages. Furthermore, the mAb upregulated the expression of MHC-II by PBMCs, and stimulated significant (p<0.0001 IL-1α, IL6, IL-8, and TNF-α expression by PBMCs. These results suggest that the mAb 2E4E4 can target and stimulate cells from multiple livestock species and thus, it is a potential candidate for adjuvant development. This is the first study to report an anti-swine CD40 agonistic mAb that is also broadly reactive against multiple species.

  3. Preclinical studies on the use of medicinal mushroom Ganoderma lucidum as an adjuvant in radiotherapy of cancer

    International Nuclear Information System (INIS)

    Gopakumar, G.; Martin, Femy; Antony, Sherin K.; Pillai, Thulasi G.; Nair, Cherupally Krishnan K.

    2010-01-01

    Our previous studies have demonstrated that an extract of Ganoderma lucidum occurring in South India possesses significant radioprotective property ex vivo. The present study describes the in vivo radioprotection of normal cells in tumour-bearing mice exposed to gamma radiation. Oral administration of G. lucidum extract (GLE) to tumour-bearing Swiss albino mice along with exposure to gamma radiation resulted in tumour regression. Single-cell gel electrophoresis (comet assay) on cells of normal and tumour tissues from tumour-bearing animals treated with GEE and radiation, revealed that there was significant reduction in radiation-induced damage to cellular DNA in normal tissues compared to the tumour, indicating preferential protection to normal tissues. The findings suggest the potential use of this mushroom extract as an adjuvant in radiotherapy, for tumour regression and prevention of radiation-induced cellular damages in normal tissues. (author)

  4. Does adjuvant systemic therapy with interferon-alpha for stage II-III melanoma prolong survival?

    NARCIS (Netherlands)

    Eggermont, Alexander M. M.; Punt, Cornelis J. A.

    2003-01-01

    The experience with interferon-alpha in malignant melanoma resembles, to some degree, the experience with various kinds of adjuvant immunotherapeutic agents where 25 years of phase III trials of adjuvant therapy in stage II-IIII melanoma have not defined a standard therapy. Most trials failed to

  5. Does adjuvant therapy improve overall survival for stage IA/B pancreatic adenocarcinoma?

    Science.gov (United States)

    Ostapoff, Katherine T; Gabriel, Emmanuel; Attwood, Kristopher; Kuvshinoff, Boris W; Nurkin, Steven J; Hochwald, Steven N

    2017-07-01

    Current guidelines recommend adjuvant chemotherapy for resected pancreatic adenocarcinoma (PDAC). However, no studies have addressed its survival benefit for stage I patients as they comprise IA or IB PDAC were identified. Median OS was 60.3 months (mo) for stage IA and 36.9 mo for IB. 45.5% received adjuvant chemotherapy; 19.9% received adjuvant chemoradiation. There was OS benefit for both stage IA/IB patients with adjuvant chemotherapy (HR = 0.73 and 0.76 for IA and IB, respectively, p = 0.002 and IA disease (n = 1,477, 37.8%), age ≥70 (p < 0.001), higher grade (p < 0.001), ≤10 lymph nodes examined (p = 0.008), positive margins (p < 0.001), and receipt of adjuvant chemoradiation (p = 0.002) were associated with worse OS. For stage IB patients (n = 2,432, 62.2%), similar associations were observed with the exception of adjuvant chemoradiation whereby there was no significant association (p = 0.35). Adjuvant chemotherapy was associated with an OS benefit for patients with stage I PDAC; adjuvant chemoradiation was either of no benefit or associated with worse OS. Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

  6. Current adjuvant treatment modalities for gastric cancer: From history to the future

    Science.gov (United States)

    Kilic, Leyla; Ordu, Cetin; Yildiz, Ibrahim; Sen, Fatma; Keskin, Serkan; Ciftci, Rumeysa; Pilanci, Kezban Nur

    2016-01-01

    The discrepancy between the surgical technique and the type of adjuvant chemotherapy used in clinical trials and patient outcomes in terms of overall survival rates has led to the generation of different adjuvant treatment protocols in distinct parts of the world. The adjuvant treatment recommendation is generally chemoradiotherapy in the United States, perioperative chemotherapy in the United Kingdom and parts of Europe, and chemotherapy in Asia. These options mainly rely on the United States Intergroup-0116, United Kingdom British Medical Research Council Adjuvant Gastric Infusional Chemotherapy, and the Asian Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer and Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer trials. However, the benefits were evident for only certain patients, which were not very homogeneous regarding the type of surgery, chemotherapy regimens, and stage of disease. Whether the dissimilarities in survival are attributable to surgical technique or intrinsic biological differences is a subject of debate. Regardless of the extent of surgery, multimodal therapy may offer modest survival advantage at least for diseases with lymph node involvement. Moreover, in the era of individualized treatment for most of the other cancer types, identification of special subgroups comprising those who will derive more or no benefit from adjuvant therapy merits further investigation. The aim of this review is to reveal the historical evolution and future reflections of adjuvant treatment modalities for resected gastric cancer patients. PMID:27190583

  7. Cardiac monitoring during adjuvant trastuzumab therapy: Guideline adherence in clinical practice

    NARCIS (Netherlands)

    Visser, Annemiek; van de Ven, Eline M. W.; Ruczynski, Larissa I. A.; Blaisse, Reinoud J. B.; van Halteren, Henk K.; Aben, Katja; van Laarhoven, Hanneke W. M.

    2016-01-01

    Cardiotoxicity is an important adverse effect of adjuvant breast cancer treatment with trastuzumab and three monthly left ventricular ejection fraction (LVEF) monitoring is considered mandatory. The purpose of this study was to gain insight into LVEF monitoring during adjuvant trastuzumab treatment

  8. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial

    NARCIS (Netherlands)

    Suter, Thomas M.; Procter, Marion; van Veldhuisen, Dirk J.; Muscholl, Michael; Bergh, Jonas; Carlomagno, Chiara; Perren, Timothy; Passalacqua, Rodolfo; Bighin, Claudia; Klijn, Jan G. M.; Ageev, Fail T.; Hitre, Erika; Groetz, Juergen; Iwata, Hiroji; Knap, Malgorzata; Gnant, Michael; Muehlbauer, Susanne; Spence, Alison; Gelber, Richard D.; Piccart-Gebhart, Martine J.

    2007-01-01

    Purpose The purpose of this analysis was to investigate trastuzumab- associated cardiac adverse effects in breast cancer patients after completion of ( neo) adjuvant chemotherapy with or without radiotherapy. Patients and Methods The Herceptin Adjuvant ( HERA) trial is a three- group, multicenter,

  9. Canadian Adjuvant Initiative Workshop, March 26–27, 2013—Ottawa, Canada

    Science.gov (United States)

    Krishnan, Lakshmi; Twine, Susan; Gerdts, Volker; Barreto, Luis; Richards, James C

    2014-01-01

    Novel adjuvants hold the promise for developing effective modern subunit vaccines capable of appropriately modulating the immune response against challenging diseases such as those caused by chronic and/or intracellular pathogens and cancer. Over the past decade there has been intensive research into discovering new adjuvants, however, their translation into routine clinical use is lagging. To stimulate discussion and identify opportunities for networking and collaboration among various stakeholders, a Canadian Adjuvant Initiative Workshop was held in Ottawa. Sponsored by the National Research Council Canada, Canadian Institutes of Health Research and the Vaccine Industry Committee, a two day workshop was held that brought together key Canadian and international stakeholders in adjuvant research from industry, academia and government. To discover innovation gaps and unmet needs, the presentations covered a board range of topics in adjuvant development; criteria for selection of lead adjuvant candidates from an industry perspective, discovery research across Canada, bioprocessing needs and challenges, veterinary vaccines, Canadian vaccine trial capabilities, the Canadian regulatory framework and WHO formulation laboratory experience. The workshop concluded with a discussion on the opportunity to create a Canadian Adjuvant Development Network. This report details the key discussion points and steps forward identified for facilitating adjuvant development research in Canada. PMID:24192752

  10. Aluminium based adjuvants and their effects on mitochondria and lysosomes of phagocytosing cells.

    Science.gov (United States)

    Ohlsson, Lars; Exley, Christopher; Darabi, Anna; Sandén, Emma; Siesjö, Peter; Eriksson, Håkan

    2013-11-01

    Aluminium oxyhydroxide, Al(OH)3 is one of few compounds approved as an adjuvant in human vaccines. However, the mechanism behind its immune stimulating properties is still poorly understood. In vitro co-culture of an aluminium adjuvant and the human monocytic cell line THP-1 resulted in reduced cell proliferation. Inhibition occurred at concentrations of adjuvant several times lower than would be found at the injection site using a vaccine formulation containing an aluminium adjuvant. Based on evaluation of the mitochondrial membrane potential, THP-1 cells showed no mitochondrial rupture after co-culture with the aluminium adjuvant, instead an increase in mitochondrial activity was seen. The THP-1 cells are phagocytosing cells and after co-culture with the aluminium adjuvant the phagosomal pathway was obstructed. Primary or early phagosomes mature into phagolysosomes with an internal pH of 4.5 - 5 and carry a wide variety of hydrolysing enzymes. Co-culture with the aluminium adjuvant yielded a reduced level of acidic vesicles and cathepsin L activity, a proteolytic enzyme of the phagolysosomes, was almost completely inhibited. THP-1 cells are an appropriate in vitro model in order to investigate the mechanism behind the induction of a phagocytosing antigen presenting cell into an inflammatory cell by aluminium adjuvants. Much information will be gained by investigating the phagosomal pathway and what occurs inside the phagosomes and to elucidate the ultimate fate of phagocytosed aluminium particles. © 2013.

  11. 21 CFR 178.3010 - Adjuvant substances used in the manufacture of foamed plastics.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Adjuvant substances used in the manufacture of... substances used in the manufacture of foamed plastics. The following substances may be safely used as adjuvants in the manufacture of foamed plastics intended for use in contact with food, subject to any...

  12. Safety and immunogenicity of adjuvanted inactivated split-virion and whole-virion influenza A (H5N1) vaccines in children: a phase I-II randomized trial.

    Science.gov (United States)

    Wu, Jiang; Liu, Shu-Zhen; Dong, Shan-Shan; Dong, Xiao-Ping; Zhang, Wu-Li; Lu, Min; Li, Chang-Gui; Zhou, Ji-Chen; Fang, Han-Hua; Liu, Yan; Liu, Li-Ying; Qiu, Yuan-Zheng; Gao, Qiang; Zhang, Xiao-Mei; Chen, Jiang-Ting; Zhong, Xiang; Yin, Wei-Dong; Feng, Zi-Jian

    2010-08-31

    Highly pathogenic avian influenza A virus H5N1 has the potential to cause a pandemic. Many prototype pandemic influenza A (H5N1) vaccines had been developed and well evaluated in adults in recent years. However, data in children are limited. Herein we evaluate the safety and immunogenicity of adjuvanted split-virion and whole-virion H5N1 vaccines in children. An open-labelled phase I trial was conducted in children aged 3-11 years to receive aluminum-adjuvated, split-virion H5N1 vaccine (5-30 microg) and in children aged 12-17 years to receive aluminum-adjuvated, whole-virion H5N1 vaccine (5-15 microg). Safety of the two formulations was assessed. Then a randomized phase II trial was conducted, in which 141 children aged 3-11 years received the split-virion vaccine (10 or 15 microg) and 280 children aged 12-17 years received the split-virion vaccine (10-30 microg) or the whole-virion vaccine (5 microg). Serum samples were collected for hemagglutination-inhibition (HI) assays. 5-15 microg adjuvated split-virion vaccines were well tolerated in children aged 3-11 years and 5-30 microg adjuvated split-virion vaccines and 5 microg adjuvated whole-virion vaccine were well tolerated in children aged 12-17 years. Most local and systemic reactions were mild or moderate. Before vaccination, all participants were immunologically naïve to H5N1 virus. Immune responses were induced after the first dose and significantly boosted after the second dose. In 3-11 years children, the 10 and 15 microg split-virion vaccine induced similar responses with 55% seroconversion and seroprotection (HI titer >or=1:40) rates. In 12-17 years children, the 30 microg split-virion vaccine induced the highest immune response with 71% seroconversion and seroprotection rates. The 5 microg whole-virion vaccine induced higher response than the 10 microg split-virion vaccine did. The aluminum-adjuvanted, split-virion prototype pandemic influenza A (H5N1) vaccine showed good safety and immunogenicity in

  13. Antigen sparing with adjuvanted inactivated polio vaccine based on Sabin strains.

    Science.gov (United States)

    Westdijk, Janny; Koedam, Patrick; Barro, Mario; Steil, Benjamin P; Collin, Nicolas; Vedvick, Thomas S; Bakker, Wilfried A M; van der Ley, Peter; Kersten, Gideon

    2013-02-18

    Six different adjuvants, each in combination with inactivated polio vaccine (IPV) produced with attenuated Sabin strains (sIPV), were evaluated for their ability to enhance virus neutralizing antibody titres (VNTs) in the rat potency model. The increase of VNTs was on average 3-, 15-, 24-fold with adjuvants after one immunization (serotypes 1, 2, and 3, respectively). Also after a boost immunization the VNTs of adjuvanted sIPV were on average another 7-20-27 times higher than after two inoculations of sIPV without adjuvant. The results indicate that it is feasible to increase the potency of inactivated polio vaccines by using adjuvants. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Adjuvant whole brain radiotherapy: strong emotions decide but rational studies are needed.

    Science.gov (United States)

    Brown, Paul D; Asher, Anthony L; Farace, Elana

    2008-04-01

    Brain metastases are common in cancer patients and cause considerable morbidity and mortality. For patients with limited disease and good performance status, treatment typically involves a combination of focal measures (e.g., surgical resection or radiosurgery) for the radiographically apparent disease, followed by adjuvant whole brain radiotherapy (WBRT) to treat subclinical disease. Because of concerns regarding the toxicity of WBRT, especially neurocognitive deterioration, many have advocated withholding adjuvant WBRT. Recently published studies have shed more light on the efficacy of adjuvant WBRT and the neurocognitive effects of WBRT. However, the inclusion of neurocognitive and quality-of-life data in clinical trials are still required to better define the role of adjuvant WBRT. Currently, two Phase III trials are underway, one in Europe and one in North America, that will determine the effect of adjuvant WBRT on patients' quality of life, neurocognitive function, and survival.

  15. Adjuvant Whole Brain Radiotherapy: Strong Emotions Decide But Rational Studies Are Needed

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Paul D. [Department of Radiation Oncology, Mayo Clinic, Rochester, MN (United States)], E-mail: brown.paul@mayo.edu; Asher, Anthony L [Brain and Spinal Cord Tumors Programs, Carolinas Medical Center and Presbyterian Hospital, Charlotte, NC (United States); Farace, Elana [Department of Neurosurgery, Pennsylvania State University, Penn State Milton S. Hershey Medical Center, Hershey, PA (United States)

    2008-04-01

    Brain metastases are common in cancer patients and cause considerable morbidity and mortality. For patients with limited disease and good performance status, treatment typically involves a combination of focal measures (e.g., surgical resection or radiosurgery) for the radiographically apparent disease, followed by adjuvant whole brain radiotherapy (WBRT) to treat subclinical disease. Because of concerns regarding the toxicity of WBRT, especially neurocognitive deterioration, many have advocated withholding adjuvant WBRT. Recently published studies have shed more light on the efficacy of adjuvant WBRT and the neurocognitive effects of WBRT. However, the inclusion of neurocognitive and quality-of-life data in clinical trials are still required to better define the role of adjuvant WBRT. Currently, two Phase III trials are underway, one in Europe and one in North America, that will determine the effect of adjuvant WBRT on patients' quality of life, neurocognitive function, and survival.

  16. Adjuvant Whole Brain Radiotherapy: Strong Emotions Decide But Rational Studies Are Needed

    International Nuclear Information System (INIS)

    Brown, Paul D.; Asher, Anthony L.; Farace, Elana

    2008-01-01

    Brain metastases are common in cancer patients and cause considerable morbidity and mortality. For patients with limited disease and good performance status, treatment typically involves a combination of focal measures (e.g., surgical resection or radiosurgery) for the radiographically apparent disease, followed by adjuvant whole brain radiotherapy (WBRT) to treat subclinical disease. Because of concerns regarding the toxicity of WBRT, especially neurocognitive deterioration, many have advocated withholding adjuvant WBRT. Recently published studies have shed more light on the efficacy of adjuvant WBRT and the neurocognitive effects of WBRT. However, the inclusion of neurocognitive and quality-of-life data in clinical trials are still required to better define the role of adjuvant WBRT. Currently, two Phase III trials are underway, one in Europe and one in North America, that will determine the effect of adjuvant WBRT on patients' quality of life, neurocognitive function, and survival

  17. Enhancement of the Immunogenicity and Protective Efficacy of a Mucosal Influenza Subunit Vaccine by the Saponin Adjuvant GPI-0100

    NARCIS (Netherlands)

    Liu, Heng; Patil, Harshad P.; de Vries-Idema, Jacqueline; Wilschut, Jan; Huckriede, Anke

    2012-01-01

    Identification of safe and effective adjuvants remains an urgent need for the development of inactivated influenza vaccines for mucosal administration. Here, we used a murine challenge model to evaluate the adjuvant activity of GPI-0100, a saponin-derived adjuvant, on influenza subunit vaccine

  18. Liposome-based polymer complex as a novel adjuvant: enhancement of specific antibody production and isotype switch

    Directory of Open Access Journals (Sweden)

    Chen CH

    2012-02-01

    Full Text Available Chia-Hung Chen1,*, Yu-Ling Lin1,*, Yen-Ku Liu1, Pei-Juin He2, Ching-Min Lin1, Yi-Han Chiu2, Chang-Jer Wu3, Tian-Lu Cheng4, Shih-Jen Liu5,6,**, Kuang-Wen Liao1,2,**1Institute of Molecular Medicine and Bioengineering, 2Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 3Department of Food Science, National Taiwan Ocean University, Keelung, 4Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 5National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, 6Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, , *Chia-Hung Chen and Yu-Ling Lin contributed equally to this work**Kuang-Wen Liao and Shih-Jen Liu contributed equally to this workAbstract: The aim of vaccination is to induce appropriate immunity against pathogens. Antibody-mediated immunity is critical for protection against many virus diseases, although it is becoming more evident that coordinated, multifunctional immune responses lead to the most effective defense. Specific antibody (Ab isotypes are more efficient at protecting against pathogen invasion in different locations in the body. For example, compared to other Ab isotypes, immunoglobulin (Ig A provides more protection at mucosal areas. In this study, we developed a cationic lipopolymer (liposome-polyethylene glycol-polyethyleneimine complex [LPPC] adjuvant that strongly adsorbs antigens or immunomodulators onto its surface to enhance or switch immune responses. The results demonstrate that LPPC enhances uptake ability, surface marker expression, proinflammatory cytokine release, and antigen presentation in mouse phagocytes. In contrast to Freund's adjuvant, LPPC preferentially activates Th1-immunity against antigens in vivo. With lipopolysaccharides or CpG oligodeoxynucleotides, LPPC dramatically enhances the IgA or IgG2A proportion of total Ig, even in hosts that have developed

  19. Effect of bupivacaine and adjuvant drugs for regional anesthesia on nerve tissue oximetry and nerve blood flow

    Directory of Open Access Journals (Sweden)

    Wiesmann T

    2018-01-01

    values (saturation values in percent at T60, S: 91.5 [84–95]; Bupi: 76 [61–86]; BupiCloni: 84.5 [76–91]; and BupiEpi: 91 [56–92].Conclusion: The application of bupivacaine results in lower nerve blood flow, but does not induce relevant ischemia. Despite significant reductions in nerve blood flow, the addition of clonidine or epinephrine to bupivacaine had no significant impact on nerve tissue oximetry compared with bupivacaine alone. Nerve ischemia due to local anesthetics is not enhanced by the adjuvants clonidine or epinephrine. Keywords: peripheral regional anesthesia, complications, nerve blood flow, local anesthetics, adjuvants

  20. IMMUNOGENICITY OF ADJUVANT INFLUENZA VACCINE FOR PREGNANT WOMEN

    Directory of Open Access Journals (Sweden)

    M. P. Kostinov

    2017-01-01

    Full Text Available Recent epidemiological events showed that pregnant women are the most vulnerable part of population if there is the flu in the country and they die much more often than the rest part of people. That is why influenza vaccination of population including pregnant women is one of the priorities of public health service in our state. Worldwide experience of influenza vaccination of either adults or children by new adjuvant vaccine has caused our research of its efficiency among pregnant women. The aim of the study was to investigate the level of antibodies to influenza virus strain A/H1N1/v, A/H3N2 and B in pregnant women vaccinated adjuvant trivalent subunit vaccine. Our research is randomized and comparative on parallel groups. It was carried out within the demands of Russian Federation and International ethic norms adapted to such kind of researches. Evaluation of the immunogenicity of the vaccine was conducted in 27 pregnant women in the II trimester of gestation, and in 23 pregnant women in the III trimester of gestation, 19 non-pregnant women was in the control group. The level of antibodies in the serum was determined using a reaction of hemagglutination inhibition before and 1, 3, 6, 9 and 12 months after the vaccination. Revealed that influenza vaccination of pregnant women in the II and III trimester, causes the increase in titers of antibodies to vaccine influenza strains A and B, to fully meet the required criteria CPMP, and does not differ from the nonpregnant group. In a month after vaccination the level of seroprotective against A/H1N1/v was 77.0%, A/H3N2 — 88.9%, B — 85.2% after vaccination in II trimester, and 87.0; 87.0; 91.35% in III trimester of gestation. The factor of seroconversion after vaccination in II trimester for A/H1N1/v was equal to 6.5, A/H3N2 — 7.2, B — 6.5, after vaccination in III trimester of pregnancy: 7.1, 6.5 and 5.1 correspondingly. At the same time revealed accelerated decline in antibody titer against

  1. Experimental study on oral sulfhydryl as an adjuvant for improving nitrate ester tolerance in an animal model.

    Science.gov (United States)

    Chen, L; Jiang, J-Q; Zhang, Y; Feng, H

    2018-03-01

    As an initial step in exploring the feasibility of oral sulfhydryl as an adjuvant for improving nitrate ester tolerance, this study was designed to experimentally test the adjuvant therapy in a rabbit model of atherosclerosis (AS). New Zealand white rabbits with induced AS were randomly divided into four groups: AS group, AS + nitrate ester group, AS + nitrate ester tolerance group, and AS + drug combination group. Additionally, four equivalent groups with healthy New Zealand white rabbits without AS were also conformed. After feeding the animals for 5 days, the concentrations of superoxide anion (•O2-), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and endothelin-1 (ET-1) in blood and the relaxation response of the aortic ring were determined in each subject. The vascular plaques in different treatment groups were assessed by Hematoxylin and eosin (HE) staining to investigate the therapeutic value of sulfhydryl as coadjuvant for improving nitrate ester tolerance, and changes in blood vessels in different treatment groups were studied by immunohistochemical assays. Our results showed no significant differences through time in the concentrations of •O2-, SOD, MDA, NO, ET-1 between the healthy control and the nitrate ester groups (p > 0.05). The levels of SOD and MDA in the nitrate ester tolerance group increased with time, however, the levels of •O2-, NO and ET-1 decreased gradually (p tolerance groups were significantly decreased, but SOD and MDA were significantly increased (p tolerance, and this strategy was safe and looks promising for humans.

  2. Adjuvant effects of recombinant giant panda (Ailuropoda melanoleuca) IL-18 on the canine distemper disease vaccine in mice.

    Science.gov (United States)

    Yan, Yue; Niu, Lili; Deng, Jiabo; Wang, Qiang; Yu, Jianqiu; Zhang, Yizheng; Wang, Jianxi; Chen, Jiao; Wei, Changhe; Tan, Xuemei

    2015-02-01

    Canine distemper virus (CDV) is a morbillivirus known to cause morbidity and mortality in a broad range of animals. Giant pandas (Ailuropoda melanoleuca), especially captive ones, are susceptible to natural infection with CDV. Interleukin-18 (IL-18) is a powerful adjuvant molecule that can enhance the development of antigen-specific immunity and vaccine efficacy. In this study, a giant panda IL-18 gene eukaryotic expression plasmid (pcAmIL-18) was constructed. Female BALB/c mice were muscularly inoculated with the plasmids pcAmIL-18, pcDNA3.1 and PBS, respectively. They were subsequently injected with an attenuated CDV vaccine for dogs, and the induced humoral and cellular responses were evaluated. The results showed that pcAmIL-18 remarkably improved the level of specific antibody, IFN-γ and IL-2 in mice sera, the T lymphocyte proliferation index and the percentage of CD4(+) and CD8(+) cells. These data indicated that pcAmIL-18 is a potential adjuvant that promotes specific immunity.

  3. Future of human Chlamydia vaccine: potential of self-adjuvanting biodegradable nanoparticles as safe vaccine delivery vehicles.

    Science.gov (United States)

    Sahu, Rajnish; Verma, Richa; Dixit, Saurabh; Igietseme, Joseph U; Black, Carolyn M; Duncan, Skyla; Singh, Shree R; Dennis, Vida A

    2018-03-01

    There is a persisting global burden and considerable public health challenge by the plethora of ocular, genital and respiratory diseases caused by members of the Gram-negative bacteria of the genus Chlamydia. The major diseases are conjunctivitis and blinding trachoma, non-gonococcal urethritis, cervicitis, pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, and interstitial pneumonia. The failures in screening and other prevention programs led to the current medical opinion that an efficacious prophylactic vaccine is the best approach to protect humans from chlamydial infections. Unfortunately, there is no human Chlamydia vaccine despite successful veterinary vaccines. A major challenge has been the effective delivery of vaccine antigens to induce safe and effective immune effectors to confer long-term protective immunity. The dawn of the era of biodegradable polymeric nanoparticles and the adjuvanted derivatives may accelerate the realization of the dream of human vaccine in the foreseeable future. Areas covered: This review focuses on the current status of human chlamydial vaccine research, specifically the potential of biodegradable polymeric nanovaccines to provide efficacious Chlamydia vaccines in the near future. Expert commentary: The safety of biodegradable polymeric nanoparticles-based experimental vaccines with or without adjuvants and the array of available chlamydial vaccine candidates would suggest that clinical trials in humans may be imminent. Also, the promising results from vaccine testing in animal models could lead to human vaccines against trachoma and reproductive diseases simultaneously.

  4. Disodium cromoglycate may act as a novel adjuvant for UV-attenuated Toxoplasma gondii vaccine in mouse model.

    Science.gov (United States)

    Li, Xi; Wu, Yifan; Huang, Shiguang; Lu, Fangli

    2018-06-01

    We have proven the beneficial effects during acute Toxoplasma gondii infection when mast cells were inhibited by disodium cromoglycate (DSCG). Here we investigated the adjuvant effect of DSCG on the protective efficacy of UV-attenuated T. gondii (UV-Tg) vaccine. Mice were infected with 10 2 Tg alone or infected with 10 2 Tg plus DSCG (Tg + DSCG), immunized with 10 5 UV-Tg and challenged with 10 2 Tg (UV-Tg + Tg) or immunized with 10 5 UV-Tg plus DSCG and challenged with 10 2 Tg (UV-Tg + DSCG + Tg). Compared to Tg group, Tg + DSCG, UV-Tg + Tg, and UV-Tg + DSCG + Tg showed significantly prolonged survival times, decreased parasite burdens, reduced liver histopathologies, and increased levels of Th1 and Th2 cytokines and IL-17 in the livers and spleens by using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Compared to UV-Tg + Tg, UV-Tg + DSCG + Tg had significantly longer survival time, lower tissue parasite burden and histopathological score, and higher levels of Th1 and Th2 cytokines and IL-17 in the livers or spleens. Our data suggest that DSCG may play an adjuvant role in the immunization induced by UV-attenuated T. gondii in mice, by promoting cellular immune response against T. gondii challenge. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Nano-self-assemblies based on synthetic analogues of mycobacterial monomycoloyl glycerol and DDA: Supramolecular structure and adjuvant efficacy

    DEFF Research Database (Denmark)

    Martin-Bertelsen, Birte; Korsholm, Karen Smith; Christensen, Dennis

    2016-01-01

    responses. In the present study, we investigated the supramolecular structure and in vivo adjuvant activity of dispersions based on binary mixtures of DDA and an array of synthetic MMG-1 analogues (MMG- 2/3/5/6) displaying longer (MMG-2) or shorter (MMG-3) alkyl chain lengths, or polar headgroup (MMG-5...... for DDA:MMG-3, depending on the DDA:MMG molar ratio. The studies also showed that ULVs were formed, regardless of the structural characteristics of the neat MMG analogues in excess buffer [lamellar (MMG-1/2/5) or inverse hexagonal (MMG-3/6) phases]. Immunization of mice with a chlamydia antigen surface......-adsorbed to DDA:MMG-1/3/6 dispersions revealed that all tested adjuvants were immunoactive and induced strong Th1 and Th17 responses with a potential for a central effector memory profile. The MMG-1 and MMG-6 analogues were equally immunoactive in vivo upon incorporation into DDA liposomes, despite the reported...

  6. Role of Bifidobacterium bifidum and plant food extracts in improving microflora and biochemical and cytogenetic parameters in adjuvant arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Al-Okbi, S. Y.; Mohamed, D. A.; Donya, S. M.; Abd El Khalek, A. B.

    2011-07-01

    The aim of the present research was to discover plant food extracts and probiotics that may have bioactivity towards chronic inflammation. Three plant food extract mixtures expected to be rich in phenolic compounds, carotenoids and tocopherols were prepared. The anti-inflammatory activity of the different mixtures as well as probiotic bacteria (Bifidobacterium bifidum) were evaluated in adjuvant arthritis in rats. The anti-inflammatory effect, mechanism of action and safety of the three mixtures and Bifidobacterium bifidum were studied by measuring the size of inflammation and the determination of inflammatory and oxidative stress biomarkers, colonic bacteria profile and specific cytogenetic parameters. The contents of tocopherols, {beta}-carotene and phenolic compounds in the mixtures were determined. The results show that the tested mixtures and Bifidobacterium bifidum possess promising anti-inflammatory effects. The mechanism of action seems to involve a reduction in oxidative stress and inflammatory bio markers and an effect on colonic microflora. Genotoxicity and DNA fragmentation induced by adjuvant arthritis were prevented after supplementation with the tested mixtures. (Author) 61 refs.

  7. Use of a Th1 Stimulator Adjuvant for Vaccination against Neospora caninum Infection in the Pregnant Mouse Model

    Directory of Open Access Journals (Sweden)

    Denis Grandgirard

    2013-03-01

    Full Text Available Vertical transmission from an infected cow to its fetus accounts for the vast majority of new Neospora caninum infections in cattle. A vaccine composed of a chimeric antigen named recNcMIC3-1-R, based on predicted immunogenic domains of the two microneme proteins NcMIC1 and NcMIC3, the rhoptry protein NcROP2, and emulsified in saponin adjuvants, significantly reduced the cerebral infection in non-pregnant BALB/c mice. Protection was associated with a mixed Th1/Th2-type cytokine response. However, the same vaccine formulation elicited a Th2-type immune response in pregnant mice and did not prevent vertical transmission or disease, neither in dams nor in offspring mice. In this study, an alternative vaccine formulation containing recNcMIC3-1-R emulsified in Freund’s incomplete adjuvant, a stimulator of the cellular immunity, was investigated. No protection against vertical transmission and cerebral infection in the pregnant mice and a very limited protective effect in the non-pregnant mice were observed. The vaccine induced a Th1-type immune response characterized by high IgG2a titres and strong IFN-γ expression, which appeared detrimental to pregnancy.

  8. Definite vs adjuvant radiotherapy. Comparative effects on lymphocyte subpopulations in patients with head and neck squamous carcinoma

    International Nuclear Information System (INIS)

    Wolf, G.T.; Amendola, B.E.; Diaz, R.; Lovett, E.J. III; Hammerschmidt, R.M.; Peterson, K.A.

    1985-01-01

    The recent association of alterations in T-lymphocyte subpopulations and impaired cellular immunity prompted an investigation of the effects of radiotherapy (RT) on serial levels of lymphocyte subsets in 30 patients with head and neck squamous carcinoma. Percentage and absolute levels of T3, T4, T6, T8, T10, T11, and Leu 7 cells were measured before, during, and after RT at monthly intervals for six months and compared with levels in 40 normal subjects. Sixteen patients received curative and 14 postoperative adjuvant RT. Before treatment, mean subset levels were similar among the patient and normal groups except for elevated Leu 7 (natural killer) cells in patients with stage I and II disease. There were profound decreases in absolute levels of each subpopulation during and after RT. The percentage of T4 (helper/inducer) cells decreased, whereas that of T8 (cytotoxic/suppressor) and Leu 7 cells tended to increase. Compared with normal values, the mean T4/T8 ratio decreased significantly by six months after RT, when absolute levels of the subsets had rebounded to pretreatment levels in the definitive RT group but remained profoundly decreased in the adjuvant group. The differing recovery patterns suggest that factors other than RT may contribute to persistent immunosuppression following RT

  9. Adjuvant psychological therapy in long-term endocrine conditions.

    Science.gov (United States)

    Daniels, J; Turner-Cobb, J M

    2017-06-01

    Consideration of psychological distress in long-term endocrine conditions is of vital importance given the prevalence of anxiety and depression in such disorders. Poor mental health can lead to compromised self-care, higher utilization of health services, lower rates of adherence, reduced quality of life and ultimately poorer outcomes. Adjuvant psychological therapy offers an effective resource to reduce distress in endocrine conditions. While the vast majority of work in this area has focused on psychological screening and intervention in diabetes, identification and recognition of psychological distress are equally important in other endocrinological conditions, with supportive evidence in polycystic ovary syndrome and Addison's disease. Referral pathways and recommendations set out by UK guidelines and the Department of Health mandate requires greater attention across a wider range of long-term endocrine conditions to facilitate improved quality of life and health outcome. © 2017 John Wiley & Sons Ltd.

  10. Cardiotoxicity in Asymptomatic Patients Receiving Adjuvant 5-fluorouracil

    DEFF Research Database (Denmark)

    Nielsen, Karin; Polk, Anne; Nielsen, Dorte Lisbet

    2014-01-01

    Evolving evidence of cardiotoxicity in cancer patients treated with 5-fluorouracil (5-FU) has been reported. We report two different clinical manifestations of asymptomatic 5-FU-associated cardiotoxicity in patients operated for colorectal cancer and treated with adjuvant chemotherapy of 5-FU...... (bolus-injection and continuous infusion for 46 hours), folinic acid and oxaliplatin (FOLFOX). For a research study evaluating cardiac events during 5-FU treatment, Holter monitoring, electrocardiogram (ECG) and echocardiography were done and cardiac markers monitored before and during the first...... and hyperlipidemia as well as an incidental finding of negative T-waves in electrocardiogram years before 5-FU treatment. No subjective cardiac symptoms were described during infusion, but approximately 12 hours after infusion she suffered from cardiac arrest but was revived. Subsequent analysis of the Holter...

  11. Effect of synthetic adjuvants of biological activity of spleen proteins

    International Nuclear Information System (INIS)

    Kartasheva, A.L.; Yuferova, N.V.; Drozhennikov, V.A.; Orlova, E.B.; Perevezentseva, O.S.; Filatov, P.P.

    1981-01-01

    Intraperitoneal administration to mice of synthetic adjuvants of a polyanion type increases the spleen mass by 500% and rises the content of proteins with activity of inhibitor of DNAase 1. A protein fraction isolated from the spleen of treated animals administered to exposed (7.7 Gy) mice alone or in a combination with exogenous DNA increases survival up to 61.1 and 80.5%, respectively, as opposed to 36.6% in the case of administration of proteins from intact animals, or 8.3% in the control (no treatment). The protein fraction from treated animals administered to mice exposed to 5.1-5.5 Gy accelerates the recovery of hemopoesis and immune response better than proteins of intact animals

  12. Musculoskeletal Adverse Events Associated with Adjuvant Aromatase Inhibitors

    Directory of Open Access Journals (Sweden)

    Qamar J. Khan

    2010-01-01

    Full Text Available Musculoskeletal symptoms including arthralgia and myalgia occur frequently in aging women, particularly during the transition to menopause, when plasma estrogens precipitously decline. In postmenopausal women (PMW with breast cancer, third-generation aromatase inhibitors (AIs as adjuvant hormonal therapy have proven to be more effective, and to have a more predictable side effect profile, than tamoxifen. However, AIs further reduce plasma estrogens in PMW, exacerbating musculoskeletal symptoms. Clinical trial data have shown significantly higher incidences of arthralgia and myalgia with AIs compared with women on tamoxifen or placebo. Symptoms may be severe enough to significantly affect quality of life; musculoskeletal symptoms are a frequent reason for discontinuing therapy. In many cases, symptoms can be effectively managed with oral analgesics or other strategies. Early recognition and effective management of musculoskeletal symptoms can help maximize treatment compliance, enabling patients to derive optimal benefit from therapy in terms of preventing recurrence.

  13. Hypofractionated Adjuvant Whole Breast Radiotherapy: Progress and Prospects

    International Nuclear Information System (INIS)

    Yarnold, John; Haviland, Joanne

    2010-01-01

    Published results of randomised trials involving >7000 women confirm the safety and efficacy of hypofractionated schedules of adjuvant radiotherapy for women with early breast cancer using fraction sizes between 2 and 3 Gy assuming appropriate downward adjustments to total dose. Unnecessary concerns relating to heart tolerance, suboptimal dose distribution and duration of follow up need not discourage the routine adoption of 15- or 16-fraction schedules in women treated by breast conservation surgery for early breast cancer. Regardless of fractionation regimen, dose escalation to the index quadrant in high risk subgroups will result in a greater relative increase in late adverse effects than tumour control, a therapeutic disadvantage that can only be overcome by exploiting a marked dose-volume effect. A 15-fraction schedule of whole breast radiotherapy is unlikely to represent the lower limits of hypofractionation, and the preliminary results of a 5-fraction regimen are encouraging

  14. The Role of Adjuvant Radiation in Uterine Sarcomas

    International Nuclear Information System (INIS)

    Sampath, Sagus; Schultheiss, Timothy E.; Ryu, Janice K.; Wong, Jeffrey Y.C.

    2010-01-01

    Purpose: To determine clinical and pathological factors significant for overall survival (OS) and local-regional failure-free survival (LRFFS) in uterine sarcoma as they relate to adjuvant radiotherapy (AR). Methods and Materials: A retrospective analysis of 3,650 patients with uterine sarcoma was conducted using the National Oncology Database, a proprietary database of aggregated tumor registries owned by Impac Medical Systems (Sunnyvale, CA). Adjuvant radiotherapy was defined as postoperative external beam radiation to the pelvis, with or without brachytherapy. Prognostic factors were identified by multivariate analysis (MVA) using the Cox proportional hazards model. The Kaplan-Meier method was used to estimate survival, with significant differences (p < 0.05) determined using the log-rank test. Results: The median follow-up time was 59 months, with a 5-year OS of 37%. Significant prognostic factors for OS were stage, race/ethnicity, grade, age, histology, lymph node status, and surgical treatment (p < 0.01 for all factors). Use of AR was not predictive for OS. For nonmetastatic cancer patients receiving definitive surgery (n = 2,206), the 5-year LRFFS was 87%. In this group, stage, grade, histology, and AR were prognostic for LRFFS (p < 0.05), with AR associated with improved outcome compared with surgery alone (hazard ratio = 0.4, p < 0.001). Patients with carcinosarcoma, endometrial stromal sarcoma, leiomyosarcoma, poorly differentiated tumors, and negative lymph nodes had reduced local-regional failure (LRF) with AR (log-rank, p < 0.05 for all). Conclusion: In the largest retrospective analysis of uterine sarcoma published thus far, AR conferred a 53% reduction in the risk of LRF at 5 years. Use of AR may have broader indications than what are currently accepted in clinical practice.

  15. Therapeutic Potential of Ginsenosides as an Adjuvant Treatment for Diabetes

    Science.gov (United States)

    Bai, Litao; Gao, Jialiang; Wei, Fan; Zhao, Jing; Wang, Danwei; Wei, Junping

    2018-01-01

    Ginseng, one of the oldest traditional Chinese medicinal herbs, has been used widely in China and Asia for thousands of years. Ginsenosides extracted from ginseng, which is derived from the roots and rhizomes of Panax ginseng C. A. Meyer, have been used in China as an adjuvant in the treatment of diabetes mellitus. Owing to the technical complexity of ginsenoside production, the total ginsenosides are generally extracted. Accumulating evidence has shown that ginsenosides exert antidiabetic effects. In vivo and in vitro tests revealed the potential of ginsenoside Rg1, Rg3, Rg5, Rb1, Rb2, Rb3, compound K, Rk1, Re, ginseng total saponins, malonyl ginsenosides, Rd, Rh2, F2, protopanaxadiol (PPD) and protopanaxatriol (PPT)-type saponins to treat diabetes and its complications, including type 1 diabetes mellitus, type 2 diabetes mellitus, diabetic nephropathy, diabetic cognitive dysfunction, type 2 diabetes mellitus with fatty liver disease, diabetic cerebral infarction, diabetic cardiomyopathy, and diabetic erectile dysfunction. Many effects are attributed to ginsenosides, including gluconeogenesis reduction, improvement of insulin resistance, glucose transport, insulinotropic action, islet cell protection, hepatoprotective activity, anti-inflammatory effect, myocardial protection, lipid regulation, improvement of glucose tolerance, antioxidation, improvement of erectile dysfunction, regulation of gut flora metabolism, neuroprotection, anti-angiopathy, anti-neurotoxic effects, immunosuppression, and renoprotection effect. The molecular targets of these effects mainly contains GLUTs, SGLT1, GLP-1, FoxO1, TNF-α, IL-6, caspase-3, bcl-2, MDA, SOD, STAT5-PPAR gamma pathway, PI3K/Akt pathway, AMPK-JNK pathway, NF-κB pathway, and endoplasmic reticulum stress. Rg1, Rg3, Rb1, and compound K demonstrated the most promising therapeutic prospects as potential adjuvant medicines for the treatment of diabetes. This paper highlights the underlying pharmacological mechanisms of the

  16. Adjuvant radiation therapy versus surgery alone in operable breast cancer

    International Nuclear Information System (INIS)

    Rutqvist, L.E.; Pettersson, D.; Johansson, H.

    1993-01-01

    This paper presents long-term results from a randomized trial of pre- or postoperative megavoltage radiation therapy versus surgery alone in pre- and postmenopausal women with operable breast cancer. Treatment outcome after relapse among patients who developed loco-regional recurrences was also analyzed. A total of 960 patients were included in the trial. The mean follow-up was 16 years (range: 13-19 years). The radiation therapy was individually planned. It included the chest wall (and the breast in the preoperative cases) and the regional lymph nodes. The tumor dose was 45 Gy/5 weeks. No adjuvant systemic therapy was used. The results showed a significant benefit with radiation therapy in terms of recurrence-free survival during the entire follow-up period. There was also an overall survival difference - corresponding to 16% reduction of deaths - in favour of the irradiated patients which, however, was not statistically significant (p=0.09). Among those 169 patients who developed loco-regional recurrences long-term control was only achieved in about one-third of the cases. This figure was similar among those who had received adjuvant radiation therapy (34%) compared to those initially treated with surgery alone (32%). This implied that the overall proportion of patients who eventually developed uncontrolled local disease was significantly higher among those initially allocated to surgery alone (16%) compared to those allocated to pre- or postoperative radiation therapy (6%, p<0.01). These results suggest that local undertreatment may be deleterious in subgroups of patients. (author) 5 tabs

  17. Adjuvant radiation therapy for pancreatic cancer: a 15-year experience

    International Nuclear Information System (INIS)

    Dobelbower, Ralph R.; Merrick, Hollis W.; Khuder, Sadik; Battle, Joyce A.; Herron, Lisa M.; Pawlicki, Todd

    1997-01-01

    Purpose: A retrospective analysis to determine differences in survival of patients with pancreatic aden carcinoma treated by radical surgery with and without adjuvant radiation therapy. Methods and Materials: Between 1980 and 1995, 249 patients with pancreatic tumors were identified at the Medical College of Ohio. Forty-four of these patients underwent radical surgical procedures with curative intent. These patients were divided into four groups according to treatment: surgery alone (n = 14), surgery plus intraoperative radiation therapy (IORT) (n = 6), surgery plus external beam radiation therapy (EBRT) (n = 14), or surgery plus both IORT and EBRT (n = 10). Outcome and survival were analyzed among the four groups. Results: The median survival time of patients treated with radical surgery alone was 6.5 months. The median survival time for the surgery plus IORT group was 9 months; however, 33.3% (two of six) of these patients survived longer than 5 years. This survival pattern was borderline significantly better than that for the surgery alone group (p = 0.0765). The surgery plus EBRT and the surgery plus IORT and EBRT groups had median survival times of 14.5 and 17.5 months, respectively. These were significantly better than that of the surgery alone group (p = 0.0004 and p = 0.0002, respectively). The addition of radiation therapy did not affect the treatment complication rate. Conclusion: The survival of patients who were treated with radical surgery alone was significantly poorer than that of patients who received adjuvant radiation therapy. These results are consistent with other studies in the literature. Patients treated with all three modalities (surgery, IORT, and EBRT) displayed the best median survival time

  18. Anti-calmodulins and tricyclic adjuvants in pain therapy block the TRPV1 channel.

    Directory of Open Access Journals (Sweden)

    Zoltán Oláh

    2007-06-01

    Full Text Available Ca(2+-loaded calmodulin normally inhibits multiple Ca(2+-channels upon dangerous elevation of intracellular Ca(2+ and protects cells from Ca(2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca(2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca(2+-uptake via the vanilloid inducible Ca(2+-channel/inflamatory pain receptor 1 (TRPV1, which suggests that calmodulin inhibitors may block pore formation and Ca(2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced (45Ca(2+-uptake at microM concentrations: calmidazolium (broad range > or = trifluoperazine (narrow range chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially. Most likely a short acidic domain at the pore loop of the channel ori