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Sample records for combination adjuvant induces

  1. Effects of simvastatin, ezetimibe, and their combination on histopathologic alterations caused by adjuvant-induced arthritis.

    PubMed

    Barbosa, Carmem Patrícia; Ritter, Alessandra Milene; da Silva, Lorena Gimenez; Grespan, Renata; Cuman, Roberto Kenji Nakamura; Hernandes, Luzmarina; Bersani-Amado, Ciomar Aparecida

    2014-08-01

    The objective of the present study was to investigate the effects of monotherapy with simvastatin or ezetimibe compared with those of an ezetimibe + simvastatin combination on the histopathologic aspects of arthritis induced by Complete Freund's Adjuvant in rats. The characteristics of diarthrosis were analyzed 7 and 28 days after arthritis induction with regard to the regularity and integrity of articular cartilage, the presence of leukocytes in blood vessels at the inflammation site, and the cytokine levels in articular tissue. Monotherapy with simvastatin or ezetimibe and the ezetimibe + simvastatin combination effectively reduced the cytokine levels (interleukin-6 and tumor necrosis factor) and articular lesions that are characteristic of this experimental disease. Although the results did not reveal significant differences between the monotherapy and the combined therapy, they suggest that these drugs have considerable antiinflammatory properties, as reflected by an attenuation of articular cartilage lesions mediated by a reduction in the levels of proinflammatory cytokines.

  2. Combination of carvacrol with methotrexate suppresses Complete Freund's Adjuvant induced synovial inflammation with reduced hepatotoxicity in rats.

    PubMed

    Banji, Otilia J F; Banji, David; Soumya, N; Chilipi, Kiran Kumar; Kalpana, C H; Kranthi Kumar, C H; Annamalai, A R

    2014-01-15

    The present study evaluated the therapeutic benefit of the combination of carvacrol, an isoprenoid having potential anti-inflammatory action, with methotrexate in suppressing Complete Freund's Adjuvant induced arthritis and attenuating methotrexate induced hepatic damage. Arthritis was induced in rats with Complete Freund's Adjuvant. Animals received methotrexate (2mg/kg) intraperitonealy once a week for 5 weeks alone and along with carvacrol orally (50 and 100mg/kg) respectively from the 10th to the 42nd day. Control and carvacrol alone group were also studied. Paw volume, hypernociception, and erythrocyte sedimentation rate were evaluated as arthritic markers. Hepatic marker enzymes in serum; myeloperoxidase, protein oxidation, and oxidative measures were determined in the liver homogenate. Liver histological assessments were also carried out. Methotrexate significantly controlled arthritis; however, liver damage was evident due to oxidative stress and rise in myeloperoxidase levels. Carvacrol suppressed the hyperalgesic response, significantly alleviated arthritis and reduced damage to the hepatocytes owing to a decline in the levels of myeloperoxidase and oxidative markers. High dose of the combination reduced the levels of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and alkaline phosphatase by 24.74%, 30.2% and 28.14% compared with methotrexate treatment. Histological assessment also revealed that carvacrol minimizes methotrexate induced liver toxicity. In combination, carvacrol promoted the anti-arthritic action of methotrexate, reduced neutrophils infiltration and peroxidative damage to the liver. Therefore, carvacrol can serve as a useful adjuvant and promote the safe use of methotrexate in the management of arthritis.

  3. Vaccination with toxofilin DNA in combination with an alum-monophosphoryl lipid A mixed adjuvant induces significant protective immunity against Toxoplasma gondii.

    PubMed

    Song, Pengxia; He, Shenyi; Zhou, Aihua; Lv, Gang; Guo, Jingjing; Zhou, Jian; Han, Yali; Zhou, Huaiyu; Hao, Zhen; Cong, Hua

    2017-01-05

    A widely prevalent disease, toxoplasmosis poses serious health threats to both humans and animals; therefore, development of an ideal DNA vaccine against Toxoplasma gondii is needed eagerly. The purpose of the present study is to assess the protective efficacy of a DNA vaccine encoding the T. gondii toxofilin gene (pEGFP-toxofilin). In addition, toxofilin DNA vaccine combined with the individual adjuvants, alum or monophosphoryl lipid A (MPLA), or a mixture of alum-MPLA adjuvant were screened for their ability to enhance antibody responses. Using bioinformatics, we analyzed the gene and amino acid sequences of the toxofilin protein, recognizing and identifying several potential linear B and T helper (Th)-1 cell epitopes. BALB/c mice were immunized three times with either toxofilin DNA vaccine alone or in combination with the adjuvants such as alum, MPLA or an alum-MPLA mixture. The systemic immune response was evaluated by cytokine, the percentage of CD4 (+) and CD8 (+) T cells and specific antibody measurement. Two weeks after the last immunization, protective efficacy was evaluated by challenging intraperitoneally with 1 × 10(4) tachyzoites of T. gondii or intragastrically with 20 cysts of T. gondii PRU strain. All experimentally immunized mice developed strong humoral and cellular immune responses compared with the control groups. Moreover, by comparison with the non-adjuvant toxofilin DNA vaccine group, adding alum adjuvant to toxofilin DNA vaccine resulted in an increase in humoral response and a skewed Th2 response. However, the MPLA adjuvant with toxofilin DNA vaccine induced significantly enhanced humoral and Th1-biased immune responses. Importantly, the co-administration of alum-MPLA adjuvant in combination with the toxofilin DNA vaccine shifted the Th2 immune response to a Th1 response compared with the alum-toxofilin group, and elicited the strongest humoral and Th1 responses among all the groups. At the same time, a longer survival time and less

  4. Mixed Adjuvant Formulations Reveal a New Combination That Elicit Antibody Response Comparable to Freund's Adjuvants

    PubMed Central

    Lai, Rachel P. J.; Seaman, Michael S.; Tonks, Paul; Wegmann, Frank; Seilly, David J.; Frost, Simon D. W.; LaBranche, Celia C.; Montefiori, David C.; Dey, Antu K.; Srivastava, Indresh K.; Sattentau, Quentin; Barnett, Susan W.; Heeney, Jonathan L.

    2012-01-01

    Adjuvant formulations capable of inducing high titer and high affinity antibody responses would provide a major advance in the development of vaccines to viral infections such as HIV-1. Although oil-in-water emulsions, such as Freund's adjuvant (FCA/FIA), are known to be potent, their toxicity and reactogenicity make them unacceptable for human use. Here, we explored different adjuvants and compared their ability to elicit antibody responses to FCA/FIA. Recombinant soluble trimeric HIV-1 gp140 antigen was formulated in different adjuvants, including FCA/FIA, Carbopol-971P, Carbopol-974P and the licensed adjuvant MF59, or combinations of MF59 and Carbopol. The antigen-adjuvant formulation was administered in a prime-boost regimen into rabbits, and elicitation of antigen binding and neutralizing antibodies (nAbs) was evaluated. When used individually, only FCA/FIA elicited significantly higher titer of nAbs than the control group (gp140 in PBS (p<0.05)). Sequential prime-boost immunizations with different adjuvants did not offer improvements over the use of FCA/FIA or MF59. Remarkably however, the concurrent use of the combination of Carbopol-971P and MF59 induced potent adjuvant activity with significantly higher titer nAbs than FCA/FIA (p<0.05). This combination was not associated with any obvious local or systemic adverse effects. Antibody competition indicated that the majority of the neutralizing activities were directed to the CD4 binding site (CD4bs). Increased antibody titers to the gp41 membrane proximal external region (MPER) and gp120 V3 were detected when the more potent adjuvants were used. These data reveal that the combination of Carbopol-971P and MF59 is unusually potent for eliciting nAbs to a variety of HIV-1 nAb epitopes. PMID:22509385

  5. Duration of immunity induced by an adjuvanted and inactivated equine influenza, tetanus and equine herpesvirus 1 and 4 combination vaccine.

    PubMed

    Heldens, J G; Kersten, A J; Weststrate, M W; van den Hoven, R

    2001-11-01

    An adjuvanted vaccine containing inactivated equine influenza, herpesvirus antigens, and tetanus toxoid was administered to young seronegative foals of 8 months of age by deep intramuscular injection in the neck (Group A). The first two vaccinations were given 4 weeks apart. The third was administered 6 months later. Another group of foals (Group B) was vaccinated according to the same scheme at the same time with monovalent equine herpes virus (EHV) vaccine (EHV1.4) vaccine. Antibody responses to the equine influenza (single radial haemolysis; SRH) and tetanus (ToBi ELISA) components of the vaccines were examined from first vaccination until 1 year after the third vaccination. The influenza components of the combination vaccine induced high antibody titres at two weeks after the second vaccination whereafter titres declined until the time of the third vaccination. After the third vaccination, the titres rose rapidly again to remain high for at least 1 year. Antibody titres against tetanus peaked only after the third vaccination but remained high enough to offer protective immunity for at least 1 year. Foals vaccinated with monovalent EHV1.4 remained seronegative for influenza and tetanus throughout the study. Four and a half months after the third vaccination of groups A and B, a third group of animals was vaccinated twice with monovalent EHV1.4 vaccine 4 weeks apart (Group C). Two weeks after the administration of the second dose in the later group, all groups (A, B, C and an unvaccinated control group D) were challenged with EHV-4. Vaccinated foals (Group A, B, C) showed a clear reduction of clinical symptoms and virus excretion after EHV-4 challenge compared with the unvaccinated control foals. No difference could be demonstrated among the vaccinated groups, suggesting that the combination vaccine protects as well as the monovalent vaccine. In EHV1.4-vaccinated foals both antigenic fractions induced clear protection up to 6 months after vaccination (9). It can

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

    NASA Astrophysics Data System (ADS)

    Yang, Deng-Fu; Hsu, Yih-Chih

    2012-03-01

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

  7. Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice

    PubMed Central

    Zhu, Qing; Egelston, Colt; Gagnon, Susan; Sui, Yongjun; Belyakov, Igor M.; Klinman, Dennis M.; Berzofsky, Jay A.

    2010-01-01

    TLR ligands are promising candidates for the development of novel vaccine adjuvants that can elicit protective immunity against emerging infectious diseases. Adjuvants have been used most frequently to increase the quantity of an immune response. However, the quality of a T cell response can be more important than its quantity. Stimulating certain pairs of TLRs induces a synergistic response in terms of activating dendritic cells and eliciting/enhancing T cell responses through clonal expansion, which increases the number of responding T cells. Here, we have found that utilizing ligands for 3 TLRs (TLR2/6, TLR3, and TLR9) greatly increased the protective efficacy of vaccination with an HIV envelope peptide in mice when compared with using ligands for only any 2 of these TLRs; surprisingly, increased protection was induced without a marked increase in the number of peptide-specific T cells. Rather, the combination of these 3 TLR ligands augmented the quality of the T cell responses primarily by amplifying their functional avidity for the antigen, which was necessary for clearance of virus. The triple combination increased production of DC IL-15 along with its receptor, IL-15Rα, which contributed to high avidity, and decreased expression of programmed death–ligand 1 and induction of Tregs. Therefore, selective TLR ligand combinations can increase protective efficacy by increasing the quality rather than the quantity of T cell responses. PMID:20101095

  8. Systemic immunotoxicity reactions induced by adjuvanted vaccines.

    PubMed

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

    2014-05-01

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

  9. Intranasal immunization of young mice with a multigene HIV-1 vaccine in combination with the N3 adjuvant induces mucosal and systemic immune responses.

    PubMed

    Bråve, Andreas; Hallengärd, David; Schröder, Ulf; Blomberg, Pontus; Wahren, Britta; Hinkula, Jorma

    2008-09-19

    One of the major challenges for the development of an HIV vaccine is to induce potent virus-specific immune responses at the mucosal surfaces where transmission of virus occurs. Intranasal delivery of classical vaccines has been shown to induce good mucosal antibody responses, but so far for genetic vaccines the success has been limited. This study shows that young individuals are sensitive to nasal immunization with a genetic vaccine delivered in a formulation of a lipid adjuvant, the Eurocine N3. Intranasal delivery of a multiclade/multigene HIV-1 genetic vaccine gave rise to vaginal and rectal IgA responses as well as systemic humoral and cellular responses. As electroporation might become the preferred means of delivering genetic vaccines for systemic HIV immunity, nasal delivery by droplet formulation in a lipid adjuvant might become a means of priming or boosting the mucosal immunity.

  10. Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy

    DTIC Science & Technology

    2012-09-01

    TITLE: Predicting the Toxicity of Adjuvant Breast Cancer Drug Combination Therapy PRINCIPAL INVESTIGATOR: Susan F Hudachek, MS, PhD...toxicity of adjuvant breast cancer drug combination therapy 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-09-1-0457 5c. PROGRAM ELEMENT NUMBER 6...breast cancer. However, co-administration of drugs , particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in

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

    PubMed Central

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

    2016-01-01

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

  12. Activation of Natural Killer T Cells by α-Galactosylceramide Rapidly Induces the Full Maturation of Dendritic Cells In Vivo and Thereby Acts as an Adjuvant for Combined CD4 and CD8 T Cell Immunity to a Coadministered Protein

    PubMed Central

    Fujii, Shin-ichiro; Shimizu, Kanako; Smith, Caroline; Bonifaz, Laura; Steinman, Ralph M.

    2003-01-01

    The maturation of dendritic cells (DCs) allows these antigen-presenting cells to initiate immunity. We pursued this concept in situ by studying the adjuvant action of α-galactosylceramide (αGalCer) in mice. A single i.v. injection of glycolipid induced the full maturation of splenic DCs, beginning within 4 h. Maturation was manifest by marked increases in costimulator and major histocompatibility complex class II expression, interferon (IFN)-γ production, and stimulation of the mixed leukocyte reaction. These changes were not induced directly by αGalCer but required natural killer T (NKT) cells acting independently of the MyD88 adaptor protein. To establish that DC maturation was responsible for the adjuvant role of αGalCer, mice were given αGalCer together with soluble or cell-associated ovalbumin antigen. Th1 type CD4+ and CD8+ T cell responses developed, and the mice became resistant to challenge with ovalbumin-expressing tumor. DCs from mice given ovalbumin plus adjuvant, but not the non-DCs, stimulated ovalbumin-specific proliferative responses and importantly, induced antigen-specific, IFN-γ producing, CD4+ and CD8+ T cells upon transfer into naive animals. In the latter instance, immune priming did not require further exposure to ovalbumin, αGalCer, NKT, or NK cells. Therefore a single dose of αGalCer i.v. rapidly stimulates the full maturation of DCs in situ, and this accounts for the induction of combined Th1 CD4+ and CD8+ T cell immunity to a coadministered protein. PMID:12874260

  13. Enzyme and combination therapy with cyclosporin A in the rat developing adjuvant arthritis.

    PubMed

    Rovenská, E; Svík, K; Stancíková, M; Rovenský, J

    1999-01-01

    Recent knowledge of the pathophysiology of rheumatoid arthritis and the mechanism of drug effects have enabled the use of new drugs and drug combinations in rheumatoid arthritis therapy. This study investigates the efficacy of both enzyme therapy and combined therapy with cyclosporin in rats with adjuvant arthritis. Rats with adjuvant-induced arthritis were administered either cyclosporin A (2.5 or 5.0 mg/kg/day per os), a mixture of enzymes (Phlogenzym (PHL); 45 mg/kg twice daily intrarectally), or a combination of 2.5 mg cyclosporin A and 90 mg PHL for a period of 40 days from the adjuvant application. Levels of serum albumin, changes in hind paw swelling and bone erosions were measured in rats as variables of inflammation and arthritis-associated destructive changes. Treatment with 5 mg of cyclosporin A, as well as with the combination therapy with cyclosporin A plus PHL, significantly inhibited both the inflammation and destructive arthritis-associated changes. However, 2.5 mg of cyclosporin A and PHL alone inhibited these disease markers, although to a lesser extent and at a later stage of arthritis development. The results show the inhibitory effect of enzyme therapy on rat adjuvant arthritis, as well as the efficacy of a low dose of cyclosporin A given in combination with enzyme therapy, which may be useful in the treatment of rheumatoid arthritis.

  14. Autoimmune/Inflammatory Syndrome Induced by Adjuvants and Thyroid Autoimmunity

    PubMed Central

    Watad, Abdulla; David, Paula; Brown, Stav; Shoenfeld, Yehuda

    2017-01-01

    The autoimmune/inflammatory syndrome induced by adjuvants (ASIA), presented by Shoenfeld and Agmon-Levin in 2011, is an entity that incorporates diverse autoimmune conditions induced by the exposure to various adjuvants. Adjuvants are agents that entail the capability to induce immune reactions. Adjuvants are found in many vaccines and used mainly to increase the response to vaccination in the general population. Silicone has also been reported to be able to induce diverse immune reactions. Clinical cases and series of heterogeneous autoimmune conditions including systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis have been reported to be induced by several adjuvants. However, only a small number of cases of autoimmune thyroid disorder have been included under the umbrella of ASIA syndrome. Indeed, clinical cases of Hashimoto’s thyroiditis and/or subacute thyroiditis were observed after the exposure to vaccines as well as silicone implantation. In our review, we aimed to summarize the current knowledge on ASIA syndrome presented as endocrinopathies, focusing on autoimmune thyroid disorders associated with the various adjuvants. PMID:28167927

  15. Effects of relaxin in a model of rat adjuvant-induced arthritis.

    PubMed

    Santora, Karen; Rasa, Cordelia; Visco, Denise; Steinetz, Bernard; Bagnell, Carol

    2005-05-01

    A reduction in the incidence and severity of rheumatoid arthritis is seen in pregnant women. Relaxin, a hormone of pregnancy, has been implicated in decreased immune responsiveness. Consequently, the effects of relaxin and estradiol valerate, alone or in combination, were assessed in the development of adjuvant-induced arthritis in the rat. Combination hormone therapy reduced adjuvant-induced paw inflammation. Radiographic analysis of the tarsal joints showed that estradiol valerate plus relaxin treatment minimized soft tissue damage and bone changes when compared to vehicle-treated arthritic controls. These results indicate that relaxin may be a factor in reducing inflammation during pregnancy.

  16. Expression of tak1 and tram induces synergistic pro-inflammatory signalling and adjuvants DNA vaccines.

    PubMed

    Larsen, Karen Colbjørn; Spencer, Alexandra J; Goodman, Anna L; Gilchrist, Ashley; Furze, Julie; Rollier, Christine S; Kiss-Toth, Endre; Gilbert, Sarah C; Bregu, Migena; Soilleux, Elizabeth J; Hill, Adrian V S; Wyllie, David H

    2009-09-18

    Improving vaccine immunogenicity remains a major challenge in the fight against developing country diseases like malaria and AIDS. We describe a novel strategy to identify new DNA vaccine adjuvants. We have screened components of the Toll-like receptor signalling pathways for their ability to activate pro-inflammatory target genes in transient transfection assays and assessed in vivo adjuvant activity by expressing the activators from the DNA backbone of vaccines. We find that a robust increase in the immune response necessitates co-expression of two activators. Accordingly, the combination of tak1 and tram elicits synergistic reporter activation in transient transfection assays. In a mouse model this combination, but not the individual molecules, induced approximately twofold increases in CD8+ T-cell immune responses. These results indicate that optimal immunogenicity may require activation of distinct innate immune signalling pathways. Thus this strategy offers a novel route to the discovery of a new generation of adjuvants.

  17. An Enhanced Synthetic Multiclade DNA Prime Induces Improved Cross-Clade-Reactive Functional Antibodies when Combined with an Adjuvanted Protein Boost in Nonhuman Primates

    PubMed Central

    Wise, Megan C.; Hutnick, Natalie A.; Pollara, Justin; Myles, Devin J. F.; Williams, Constance; Yan, Jian; LaBranche, Celia C.; Khan, Amir S.; Sardesai, Niranjan Y.; Montefiori, David; Barnett, Susan W.; Zolla-Pazner, Susan; Ferrari, Guido

    2015-01-01

    ABSTRACT The search for an efficacious human immunodeficiency virus type 1 (HIV-1) vaccine remains a pressing need. The moderate success of the RV144 Thai clinical vaccine trial suggested that vaccine-induced HIV-1-specific antibodies can reduce the risk of HIV-1 infection. We have made several improvements to the DNA platform and have previously shown that improved DNA vaccines alone are capable of inducing both binding and neutralizing antibodies in small-animal models. In this study, we explored how an improved DNA prime and recombinant protein boost would impact HIV-specific vaccine immunogenicity in rhesus macaques (RhM). After DNA immunization with either a single HIV Env consensus sequence or multiple constructs expressing HIV subtype-specific Env consensus sequences, we detected both CD4+ and CD8+ T-cell responses to all vaccine immunogens. These T-cell responses were further increased after protein boosting to levels exceeding those of DNA-only or protein-only immunization. In addition, we observed antibodies that exhibited robust cross-clade binding and neutralizing and antibody-dependent cellular cytotoxicity (ADCC) activity after immunization with the DNA prime-protein boost regimen, with the multiple-Env formulation inducing a more robust and broader response than the single-Env formulation. The magnitude and functionality of these responses emphasize the strong priming effect improved DNA immunogens can induce, which are further expanded upon protein boost. These results support further study of an improved synthetic DNA prime together with a protein boost for enhancing anti-HIV immune responses. IMPORTANCE Even with effective antiretroviral drugs, HIV remains an enormous global health burden. Vaccine development has been problematic in part due to the high degree of diversity and poor immunogenicity of the HIV Env protein. Studies suggest that a relevant HIV vaccine will likely need to induce broad cellular and humoral responses from a simple vaccine

  18. Chemotherapy of arthritis induced in rats by mycobacterial adjuvant

    PubMed Central

    Newbould, B. B.

    1963-01-01

    Arthritis induced in rats by mycobacterial adjuvant has been used for the study of compounds of known value in the treatment of rheumatoid arthritis in man. The development of the arthritic syndrome in treated and control rats was followed by measuring the changes in foot thickness of both hind-feet with a micrometer. This method allowed the effect of anti-inflammatory compounds to be expressed quantitatively. Anti-inflammatory activity was readily observed in certain steroids, pyrazolidines, salicylates and sodium aurothiomalate. Chloroquine and hydroxychloroquine were inactive. The inhibition obtained by daily treatment with the steroid paramethasone disappeared when treatment was withdrawn. ImagesFig. 1Fig. 3Fig. 4 PMID:14066137

  19. Combined effect of space radiation and adjuvants on mice in vivo

    NASA Astrophysics Data System (ADS)

    Sorokina, Svetlana; Zaichkina, Svetlana; Rozanova, Olga; Aptikaeva, Gella; Romanchenko, Sergei; Smirnova, Helene; Peleshko, Vladimir

    2012-07-01

    Recently we investigated the cytogenetic effects of low-dose-rate high-LET radiation on SHK mice in the radiation field behind the concrete shield of the Serpukhov accelerator with 70 GeV proton energy, that simulates the spectral and component composition of radiation fields formed in the conditions of high-altitude flights. It was found that low doses of high-LET irradiation led to an increase in the cytogenetic damage in mice which can be compared with level of spontaneous lesions. At the same time no decrease of cytogenetic damage was detected after irradiation with the challenging dose of 1.5 Gy, i. e., no adaptive response (AR) takes place in polychromatic erythrocytes (PCE) as opposed to low doses of chronic X-radiation. The goal of the present work was to determine if there is any influence of combined action of low doses of high-LET radiation and adjuvants on the cytogenetic damages and solid tumor growth in mice. Two-month-old SHK male mice were used. A search for potential adaptogens was performed among the adjuvants such as dibazol and calcium chloride. In each experiment, a group of animals was exposed to low doses of high-LET radiation and treated with dibazol or CaCl2 solutions after that mice were additionally irradiated with X-radiation according to the scheme of AR: 0.1 Gy + 1.5 Gy. After 28 h, the animals of all groups were killed by the cervical dislocation. Bone marrow specimens for calculating micronuclei (MN) in PCE were prepared by a conventional method with minor modifications. The influence of combined treatment of high-LET radiation and adjuvants on the growth of solid tumor of Ehrlich ascite carcinoma was estimated by measuring the size of the tumor at different times after the inoculation of ascitic cells into the femur. Our earlier study has shown that dibazol when used alone not only induced AR but also increased the magnitude of radiation AR when used in combination with low doses of X-radiation. In present work the obtained results

  20. Montanide ISA™ 201 adjuvanted FMD vaccine induces improved immune responses and protection in cattle.

    PubMed

    Dar, Pervaiz; Kalaivanan, Ramya; Sied, Nuru; Mamo, Bedaso; Kishore, Subodh; Suryanarayana, V V S; Kondabattula, Ganesh

    2013-07-18

    Despite significant advancements in modern vaccinology, inactivated whole virus vaccines for foot-and-mouth disease (FMD) remain the mainstay for prophylactic and emergency uses. Many efforts are currently devoted to improve the immune responses and protective efficacy of these vaccines. Adjuvants, which are often used to potentiate immune responses, provide an excellent mean to improve the efficacy of FMD vaccines. This study aimed to evaluate three oil adjuvants namely: Montanide ISA-201, ISA-206 (SEPPIC, France) and GAHOL (an in-house developed oil-adjuvant) for adjuvant potential in inactivated FMD vaccine. Groups of cattle (n=6) were immunized once intramuscularly with monovalent FMDV 'O' vaccine formulated in these adjuvants, and humoral (serum neutralizing antibody, IgG1 and IgG2) and cellular (lymphoproliferation) responses were measured. Montanide ISA-201 adjuvanted vaccine induced earlier and higher neutralizing antibody responses as compared to the two other adjuvants. All the adjuvants induced mainly serum IgG1 isotype antibody responses against FMDV. However, Montanide ISA-201 induced relatively higher IgG2 responses than the other two adjuvants. Lymphoproliferative responses to recall FMDV antigen were relatively higher with Montanide ISA-201, although not always statistically significant. On homologous FMDV challenge at 30 days post-vaccination, 100% (6/6) of the cattle immunized with Montanide-201 adjuvanted vaccine were protected, which was superior to those immunized with ISA-206 (66.6%, 4/6) or GAHOL adjuvanted vaccine (50%, 3/6). Virus replication following challenge infection, as determined by presence of the viral genome in oropharynx and non-structural protein serology, was lowest with Montanide ISA-201 adjuvant. Collectively, these results indicate that the Montanide ISA-201 adjuvanted FMD vaccine induces enhanced immune responses and protective efficacy in cattle. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Neurotoxicity Questions Regarding Common Peripheral Nerve Block Adjuvants in Combination with Local Anesthetics

    PubMed Central

    Knight, Joshua B.; Schott, Nicholas J.; Kentor, Michael L.; Williams, Brian A.

    2015-01-01

    Purpose of Review Outline the analgesic role of perineural adjuvants for local anesthetic nerve block injections, and evaluate current knowledge regarding whether adjuvants modulate the neurocytologic properties of local anesthetics. Recent Findings Perineural adjuvant medications such as dexmedetomidine, clonidine, buprenorphine, dexamethasone, and midazolam play unique analgesic roles. The dosing of these medications to prevent neurotoxicity is characterized in various cellular and in vivo models. Much of this mitigation may be via reducing the dose of local anesthetic used while achieving equal or superior analgesia. Dose-concentration animal models have shown no evidence of deleterious effects. Clinical observations regarding blocks with combined bupivacaine-clonidine-buprenorphine-dexamethasone have shown beneficial effects on block duration and rebound pain without long-term evidence of neurotoxicity. In vitro and in vivo studies of perineural clonidine and dexmedetomidine show attenuation of perineural inflammatory responses generated by local anesthetics. Summary Dexmedetomidine added as a peripheral nerve blockade adjuvant improves block duration without neurotoxic properties. The combined adjuvants clonidine, buprenorphine, and dexamethasone do not appear to alter local anesthetic neurotoxicity. Midazolam significantly increases local anesthetic neurotoxicity in vitro, but when combined with clonidine-buprenorphine-dexamethasone (sans local anesthetic) produces no in vitro or in vivo neurotoxicity. Further larger-species animal testing and human trials will be required to reinforce the clinical applicability of these findings. PMID:26207854

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

    PubMed

    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.

  3. 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.

    PubMed

    Thim, Hanna L; Villoing, Stéphane; McLoughlin, Marian; Christie, Karen Elina; Grove, Søren; Frost, Petter; Jørgensen, Jorunn B

    2014-03-25

    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 receptor (PRR

  4. 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

    PubMed Central

    Thim, Hanna L.; Villoing, Stéphane; McLoughlin, Marian; Christie, Karen Elina; Grove, Søren; Frost, Petter; Jørgensen, Jorunn B.

    2014-01-01

    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 receptor (PRR

  5. Adjuvant can improve protection induced by OMV vaccine against Neisseria meningitidis serogroups B/C in neonatal mice.

    PubMed

    Fukasawa, Lucila O; Dias, Waldely O; Schenkman, Rocilda P F; Raw, I; Tanizaki, Martha M

    2004-07-01

    Meningococcal outer membrane vesicle (OMV) vaccines are weak antigens in infants. This study aimed at investigating alternative adjuvants for induction of functional antibodies in newborn mice. Serogroup B/C anti-meningococcal vaccines, consisting of capsular polysaccharide from serogroup C (PSC) conjugated to OMV from one serogroup B serosubtype prevalent in Brazil, combined with OMV from another prevalent serosubtype, were tested in newborn and adult mice with the following adjuvants: aluminum hydroxide, MPL (monophosphoryl lipid A), Titermax and MF59. Total IgG, IgG avidity index determination and bactericidal assay were performed with sera from immunized mice. Antibodies induced against PSC in newborn mice showed avidity and bactericidal titers, similar to those obtained in adult mice, independently of the adjuvant. Evidence is presented that the inclusion of MF59 enhanced the immune response against OMV in newborn mice.

  6. The effect of adjuvants on the immune response induced by a DBL4ɛ-ID4 VAR2CSA based Plasmodium falciparum vaccine against placental malaria.

    PubMed

    Pinto, V V; Salanti, A; Joergensen, L M; Dahlbäck, M; Resende, M; Ditlev, S B; Agger, E M; Arnot, D E; Theander, T G; Nielsen, M A

    2012-01-11

    A vaccine protecting women against placental malaria could be based on the sub-domains of the VAR2CSA antigen, since antibodies against the DBL4ɛ-ID4 subunit of the VAR2CSA protein can inhibit parasite binding to the placental ligand chondroitin sulphate A (CSA). Here we tested the ability of DBL4ɛ-ID4 to induce binding-inhibitory antibodies when formulated with adjuvants approved for human use. We have characterized the immune response of DBL4ɛ-ID4 in combination with Freund's complete and incomplete adjuvant and with three adjuvants currently being used in clinical trials: Montanide(®) ISA 720, Alhydrogel(®) and CAF01. Antibodies induced against DBL4ɛ-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 type responses, resulting in IgG with similar binding strength, with to the DBL4ɛ-ID4 antigen. These results demonstrate that the DBL4ɛ-ID4 antigen is highly immunogenic and that binding inhibitory antibodies are induced when formulated with any of the tested adjuvants.

  7. Matrix-M™ adjuvation broadens protection induced by seasonal trivalent virosomal influenza vaccine.

    PubMed

    Cox, Freek; Saeland, Eirikur; Baart, Matthijs; Koldijk, Martin; Tolboom, Jeroen; Dekking, Liesbeth; Koudstaal, Wouter; Lövgren Bengtsson, Karin; Goudsmit, Jaap; Radošević, Katarina

    2015-12-08

    Influenza virus infections are responsible for significant morbidity worldwide and therefore it remains a high priority to develop more broadly protective vaccines. Adjuvation of current seasonal influenza vaccines has the potential to achieve this goal. To assess the immune potentiating properties of Matrix-M™, mice were immunized with virosomal trivalent seasonal vaccine adjuvated with Matrix-M™. Serum samples were isolated to determine the hemagglutination inhibiting (HAI) antibody titers against vaccine homologous and heterologous strains. Furthermore, we assess whether adjuvation with Matrix-M™ broadens the protective efficacy of the virosomal trivalent seasonal vaccine against vaccine homologous and heterologous influenza viruses. Matrix-M™ adjuvation enhanced HAI antibody titers and protection against vaccine homologous strains. Interestingly, Matrix-M™ adjuvation also resulted in HAI antibody titers against heterologous influenza B strains, but not against the tested influenza A strains. Even though the protection against heterologous influenza A was induced by the adjuvated vaccine, in the absence of HAI titers the protection was accompanied by severe clinical scores and body weight loss. In contrast, in the presence of heterologous HAI titers full protection against the heterologous influenza B strain without any disease symptoms was obtained. The results of this study emphasize the promising potential of a Matrix-M™-adjuvated seasonal trivalent virosomal influenza vaccine. Adjuvation of trivalent virosomal vaccine does not only enhance homologous protection, but in addition induces protection against heterologous strains and thus provides overall more potent and broad protective immunity.

  8. The benefit of adjuvant chemotherapy combined with postoperative radiotherapy for endometrial cancer: a meta-analysis.

    PubMed

    Park, Hyun Jong; Nam, Eun Ji; Kim, Sunghoon; Kim, Yong Bae; Kim, Young Tae

    2013-09-01

    The objective of our study was to determine whether adjuvant chemotherapy combined with postoperative radiotherapy would have benefits for the disease-free survival and overall survival in patients with high-risk endometrial cancer. Electronic searches for studies of adjuvant chemotherapy combined with postoperative radiotherapy in endometrial cancer patients between March 1971 and March 2012 were made on MEDLINE, SCOPUS, and the Cochrane library. Articles with more than 4 stars on the Newcastle-Ottawa scale or a score of more than 4 on the modified Jadad scale were included. A meta-analysis was performed, and pooled hazard ratios (HR) of progression-free survival (PFS) and overall survival (OS) between patients whose adjuvant chemotherapy was combined with radiotherapy (the CTx+RTx group) and patients with adjuvant radiotherapy only (the RTx group) were derived from the fixed effect model or random effect model. Three observational studies and 3 randomized clinical trials (RCTs) were included in the final analysis. Subgroup analysis for FIGO stage showed that the CTx+RTx group had a more significant survival benefit compared to that of the RTx group in advanced stage endometrial cancer (OS HR 0.53, 95% CI 0.36-0.80; PFS HR 0.54, 95% CI 0.37-0.77), but no significant benefit in early stage endometrial cancer (OS HR 0.96, 95% CI 0.70-1.32; PFS HR 1.00, 95% CI 0.39-2.58). This meta-analysis suggests that adjuvant chemotherapy combined with postoperative radiotherapy could probably reduce disease progression and overall death in patients with advanced-stage disease. In order to examine whether the multimodal treatment has benefit in high-risk endometrial cancer, we need further large-scale RCTs. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. ASIA or Shoenfeld's syndrome--an autoimmune syndrome induced by adjuvants.

    PubMed

    Cojocaru, M; Chicoş, B

    2013-01-01

    Recently, reports have suggested grouping different autoimmune conditions that are triggered by external stimuli as a single syndrome called autoimmune syndrome induced by adjuvants (ASIA). This syndrome is characterized by the appearance of myalgia, myositis, muscle weakness, arthralgia, arthritis, chronic fatigue, sleep disturbances, cognitive impairment and memory loss, and the possible emergence of a demyelinating autoimmune disease caused by systemic exposure after vaccines and adjuvants. As there are no markers for ASIA, the authors intend to present ASIA, or Shoenfeld's syndrome, as an autoimmune syndrome induced by adjuvants.

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

    PubMed Central

    den Brok, Martijn H.; Büll, Christian; Wassink, Melissa; de Graaf, Annemarie M.; Wagenaars, Jori A.; Minderman, Marthe; Thakur, Mayank; Amigorena, Sebastian; Rijke, Eric O.; Schrier, Carla C.; Adema, Gosse 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 induced is not clear. Here we show that SBAs uniquely induce intracellular lipid bodies (LBs) in the CD11b+ DC subset in vitro and in vivo. Using genetic and pharmacological interference in models for vaccination and in situ tumour ablation, we demonstrate that LB induction is causally related to the saponin-dependent increase in cross-presentation and T-cell activation. These findings link adjuvant activity to LB formation, aid the application of SBAs as a cancer vaccine component, and will stimulate development of new adjuvants enhancing T-cell-mediated immunity. PMID:27819292

  11. Immunogenicity characterization of the multi-epitope vaccine CTB-UE with chitosan-CpG as combination adjuvants against Helicobacter pylori.

    PubMed

    Xing, Yingying; Liu, Wei; Li, Xiaokang; Guo, Le; Lv, Xiaobo; Xi, Tao

    2015-07-03

    Urease is considered as an excellent vaccine candidate antigen against Helicobacter pylori (H. pylori) infection. Our previous study reported a novel multi-epitope vaccine CTB-UE which was composed of the mucosal adjuvant cholera toxin B subunit (CTB) and five cell epitopes from urease subunits. Murine experiments indicated that it could induce cellular and humoral immune responses intensively and attenuate H. pylori infection effectively in mice model. However, the body expression and lack of suitable adjuvant of this epitope vaccine restricted its application. In this study, new recombinant Escherichia coli strains was established to increase the solubility by fusing thioredoxin (Trx) and the combination adjuvants which composed of the chitosan and CpG were adopted to enhance the immunogenicity of CTB-UE for oral immunization. The experimental results indicated that the levels of IgG2a, IgG1 and IgA in the serum and the levels of sIgA in stomach, intestine and feces were significantly higher in the vaccinated group compared with the model control group. Additionally, chitosan-CpG combination adjuvants changed the ratio of IgG2a/IgG1 and conferred Th1/Th17-mediated protective immune responses. These results demonstrate that the oral vaccine with chitosan-CpG as combination adjuvants may be a promising vaccine candidate against H. pylori infection.

  12. Complete Freund's adjuvant-induced hyperalgesia: a human perception.

    PubMed

    Gould, H J

    2000-03-01

    Much of our current understanding about chronic pain and the mechanisms of nociception has been derived from animal models (Bennett GJ. Animal models of neuropathic pain. In: Gebhart, GF, Hammond DL, Jensen TS, editors. Progress in pain research and management, vol. 2, Proceedings of the 7th World Congress of Pain. Seattle, WA: IASP Press, 1994. pp. 495-510; Dubner R, Methods of assessing pain in animals. In: Wall PD, Melzack R, editors. Textbook of pain, vol. 3. Edinburgh: Churchill Livingstone, 1994. pp. 293-302). It has been argued in some cases that animals do not perceive 'pain' as humans do, and thus extrapolation of the results of studies in animals is invalid. Clearly, the animal models used in the laboratory do not approach the complexity of chronic pain encountered in the clinical setting. Human pain perception is more complex since it encompasses lesion variability, as well as psychosocial, cultural, developmental, and environmental variables. Where parallels exist, it is possible to gain insight into certain aspects of human pain syndromes that are likely to lead to improved therapeutic opportunities for individual patients. One such model that is frequently used in animals to study pain associated with inflammation is the subcutaneous injection of complete Freund's adjuvant (CFA). For ethical reasons, however, little information is available from humans concerning pain associated with this form of inflammation. Due to an inadvertent subcutaneous injection of CFA into the terminal phalanx of this investigator, a study with an N of 1, was conducted to compare the subjective effects of CFA-induced inflammation with objective measurements.

  13. Effective treatment of rat adjuvant-induced arthritis by celastrol

    PubMed Central

    Cascão, R.; Vidal, B.; Raquel, H.; Neves-Costa, A.; Figueiredo, N.; Gupta, V.; Fonseca, J.E.; Moita, L.F.

    2012-01-01

    We have previously reported an increase in interleukin (IL)-1β and IL-17 levels, and a continuous activation of caspase-1 in early rheumatoid arthritis (RA) patients. These results suggest that drugs targeting IL-1β regulatory pathways, in addition to tumor necrosis factor (TNF), may constitute promising therapeutic agents in early RA. We have recently used a THP-1 macrophage-like cell line to screen 2320 compounds for those that down-regulate both IL-1β and TNF secretion. Celastrol was one of the most promising therapeutic candidates identified in that study. Our main goal in the present work was to investigate whether administration of celastrol is able to attenuate inflammation in a rat model of adjuvant-induced arthritis (AIA). Moreover, since IL-1β is known to play a role in the polarization of Th17 cells, we also investigate whether administration of digoxin, a specific inhibitor of Th17 cells polarization, is able to attenuate inflammation in the same rat model. We found that celastrol administration significantly suppressed joint inflammation. The histological and immunohistochemical evaluation revealed that celastrol-treated rats had a normal joint structure with complete abrogation of the inflammatory infiltrate and cellular proliferation. In contrast, we observed that digoxin administration significantly ameliorated inflammation but only if administrated in the early phase of disease course (after 4 days of disease induction), and it was not efficient at inhibiting the infiltration of immune cells within the joint and in preventing damage. Thus, our results suggest that celastrol has significant anti-inflammatory and anti-proliferative properties and can constitute a potential anti-inflammatory drug with therapeutic efficacy in the treatment of immune-mediated inflammatory diseases such as RA. Furthermore, we find that early inhibition of Th17 cells polarization ameliorates arthritis but it is not as effective as celastrol. PMID:22415021

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

    PubMed

    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.

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

    PubMed Central

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

    2017-01-01

    Objectives: 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. Methods: 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. Results: 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. Conclusions: These methods may be useful for improving characterization approaches of antigen–adjuvant mixtures by SDS-PAGE. PMID:28515938

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

    PubMed

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

    2016-01-01

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

  17. Primary and Radiation-induced Breast Angiosarcoma: Clinicopathologic Predictors of Outcomes and the Impact of Adjuvant Radiation Therapy.

    PubMed

    Ghareeb, Erica R; Bhargava, Rohit; Vargo, John A; Florea, Anca V; Beriwal, Sushil

    2016-10-01

    Mammary angiosarcoma (AS) is an aggressive malignancy with high recurrence rates and poor overall survival. Limited data exist to guide treatment. We aimed to identify patterns of failure in the context of adjuvant radiation and to identify prognostic indicators to better guide management. Thirty-five patients with breast AS at UPMC Magee Women's Hospital from June 1994 to March 2011 were retrospectively reviewed. Pathology was rereviewed for 22 patients by an expert breast pathologist using an objective scoring system, partly based on the Rosen grading scheme. All patients completed R0 resection, with 14 of them receiving adjuvant radiotherapy (RT) (82% of which represented reirradiation for radiation-induced AS). At a median follow-up of 20 months (range, 3 to 178 mo), the primary mode of failure was local with 32% local first failure. Tumor size >5 cm, radiation-induced etiology, and the omission of adjuvant RT were important prognostic factors of tumor control and survival. Histopathology including necrosis, number of mitotic figures, endothelial tufting, solid/spindle cell foci, and the combined scoring system were prognostic for recurrence patterns. Breast AS has high rates of local failure despite R0 resection, which may be improved with adjuvant RT, even in the reirradiation setting. Histopathology is prognostic for recurrence patterns.

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

    PubMed Central

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

    2016-01-01

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

  19. Iodine and doxorubicin, a good combination for mammary cancer treatment: antineoplastic adjuvancy, chemoresistance inhibition, and cardioprotection

    PubMed Central

    2013-01-01

    Background Although mammary cancer (MC) is the most common malignant neoplasia in women, the mortality for this cancer has decreased principally because of early detection and the use of neoadjuvant chemotherapy. Of several preparations that cause MC regression, doxorubicin (DOX) is the most active, first-line monotherapeutic. Nevertheless, its use is limited due to the rapid development of chemoresistance and to the cardiotoxicity caused by free radicals. In previous studies we have shown that supplementation with molecular iodine (I2) has a powerful antineoplastic effect in methylnitrosourea (MNU)-induced experimental models of MC. These studies also showed a consistent antioxidant effect of I2 in normal and tumoral tissues. Methods Here, we analyzed the effect of I2 in combination with DOX treatment in female Sprague Dawley rats with MNU-induced MC. In the first experiment (short) animals were treated with the therapeutic DOX dose (16 mg/kg) or with lower doses (8 and 4 mg/Kg), in each case with and without 0.05% I2 in drinking water. Iodine treatment began on day 0, a single dose of DOX was injected (ip) on day 2, and the analysis was carried out on day 7. In the second experiment (long) animals with and without iodine supplement were treated with one or two injections of 4 mg/kg DOX (on days 0 and 14) and were analyzed on day 56. Results At all DOX doses, the short I2 treatment induced adjuvant antineoplastic effects (decreased tumor size and proliferating cell nuclear antigen level) with significant protection against body weight loss and cardiotoxicity (creatine kinase MB, cardiac lipoperoxidation, and heart damage). With long-term I2, mammary tumor tissue became more sensitive to DOX, since a single injection of the lowest dose of DOX (4 mg/Kg) was enough to stop tumor progression and a second DOX4 injection on day 14 caused a significant and rapid decrease in tumor size, decreased the expression of chemoresistance markers (Bcl2 and survivin), and increased

  20. Toxicity of combined treatment of adjuvant irradiation and interferon alpha2b in high-risk melanoma patients.

    PubMed

    Conill, Carlos; Jorcano, Sandra; Domingo-Domènech, Josep; Marruecos, Jordi; Vilella, Ramón; Malvehy, Josep; Puig, Susana; Sánchez, Marcelo; Gallego, Rosa; Castel, Teresa

    2007-10-01

    Surgically resected stage III melanoma patients commonly receive adjuvant therapy with interferon (IFN) alpha2b. For those patients with high-risk features of draining node recurrence, radiation therapy can also be considered as a treatment option. The purpose of this retrospective study was to assess the efficacy and radiation-related toxicity of this combined therapy. Eighteen patients receiving adjuvant IFNalpha2b therapy during radiation therapy, or within 1 month of its completion, were reviewed retrospectively and analysed for outcome. Radiation was delivered at 600 cGy dose per fraction, in 16 out of 18 patients, twice a week, and at 200 cGy dose per fraction in two patients five times a week. Total radiation dose and number of fractions were as follows: 30 Gy/5 fr (n=8), 36 Gy/6 fr (n=8) and 50 Gy/25 fr (n=2). The percentage of disease-free patients, with no local recurrence, at 3 years was 88%. In 10 patients, IFNalpha2b was administered concurrently with radiotherapy; in three, within 30 days before or after radiation; and in five, more than 30 days after radiation. All the patients experienced acute skin reactions, grade I on the Radiation Therapy Oncology Group (RTOG) scale. Late radiation-related toxicity was seen in one patient with grade III (RTOG) skin reaction and two with grade IV (RTOG) radiation-induced myelitis. Concurrent use of adjuvant radiotherapy and IFNalpha2b might enhance radiation-induced toxicity, and special care should be taken when the spinal cord is included in the radiation field.

  1. Innate-immunity cytokines induced by very small size proteoliposomes, a Neisseria-derived immunological adjuvant

    PubMed Central

    Venier, C; Guthmann, M D; Fernández, L E; Fainboim, L

    2007-01-01

    Neisserial outer membrane proteins have been combined with monosialoganglioside GM3 to form very small size proteoliposomes (VSSP), a nanoparticulated formulation used as a cancer vaccine for the treatment of cancer patients with GM3-positive tumours. VSSP were shown to elicit anti-GM3 and anti-tumour immune responses. VSSP have also been shown to be an efficient adjuvant for tumour-cell and peptide-antigen vaccines in mice. In vitro studies showed that VSSP promote maturation of both murine and human dendritic cells, suggesting that VSSP could be used as efficient adjuvants. In order to study further the capacity of VSSP to elicit innate immune responses, human peripheral blood mononuclear cells and monocytes derived thereof were assessed for in vitro secretion of interleukin (IL)-10, IL-6, IL-12 and interferon (IFN)-γ. VSSP most prominently induced the secretion of IL-6. IL-10 was secreted at a lower level. IL-12 p40 (but no p70) was also detected. IFN-γ response was observed in 56% of the tested samples. Cytokine secretion was not related to lipopolysaccharide (LPS) content and involved Toll-like receptor 2 (TLR2)-mediated signal transduction. VSSP also induced DC maturation and a cytokine secretion pattern (high IL-6/low IL-10) which differs from that induced by LPS. The observed proinflammatory cytokine secretion pattern and the capacity of VSSP to drive DC maturation are examined in the light of the properties of other bacterial derivatives currently being user for immunotherapy purposes. Our results suggest that VSSP could be tested in clinical settings where T helper 1-type immune responses would be beneficial. PMID:17223981

  2. Chitosan and Sodium Alginate Combinations Are Alternative, Efficient, and Safe Natural Adjuvant Systems for Hepatitis B Vaccine in Mouse Model

    PubMed Central

    AbdelAllah, Nourhan H.; Boseila, Abeer A.; Amin, Magdy A.

    2016-01-01

    Hepatitis B viral (HBV) infections represent major public health problem and are an occupational hazard for healthcare workers. Current alum-adjuvanted HBV vaccine is the most effective measure to prevent HBV infection. However, the vaccine has some limitations including poor response in some vaccinee and being a frost-sensitive suspension. The goal of our study was to use an alternative natural adjuvant system strongly immunogenic allowing for a reduction in dose and cost. We tested HBV surface antigen (HBsAg) adjuvanted with chitosan (Ch) and sodium alginate (S), both natural adjuvants, either alone or combined with alum in mouse model. Mice groups were immunized subcutaneously with HBsAg adjuvanted with Ch or S, or triple adjuvant formula with alum (Al), Ch, and S, or double formulations with AlCh or AlS. These were compared to control groups immunized with current vaccine formula or unadjuvanted HBsAg. We evaluated the rate of seroconversion, serum HBsAg antibody, IL-4, and IFN-γ levels. The results showed that the solution formula with Ch or S exhibited comparable immunogenic responses to Al-adjuvanted suspension. The AlChS gave significantly higher immunogenic response compared to controls. Collectively, our results indicated that Ch and S are effective HBV adjuvants offering natural alternatives, potentially reducing dose. PMID:27493674

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-08-01

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

  5. Tailoring subunit vaccine immunogenicity: maximizing antibody and T cell responses by using combinations of adenovirus, poxvirus and protein-adjuvant vaccines against Plasmodium falciparum MSP1.

    PubMed

    Douglas, Alexander D; de Cassan, Simone C; Dicks, Matthew D J; Gilbert, Sarah C; Hill, Adrian V S; Draper, Simon J

    2010-10-18

    Subunit vaccination modalities tend to induce particular immune effector responses. Viral vectors are well known for their ability to induce strong T cell responses, while protein-adjuvant vaccines have been used primarily for induction of antibody responses. Here, we demonstrate in mice using a Plasmodium falciparum merozoite surface protein 1 (PfMSP1) antigen that novel regimes combining adenovirus and poxvirus vectored vaccines with protein antigen in Montanide ISA720 adjuvant can achieve simultaneous antibody and T cell responses which equal, or in some cases surpass, the best immune responses achieved by either the viral vectors or the protein vaccine alone. Such broad responses can be achieved either using three-stage vaccination protocols, or with an equally effective two-stage protocol in which viral vectors are admixed with protein and adjuvant, and were apparent despite the use of a protein antigen that represented only a portion of the viral vector antigen. We describe further possible advantages of viral vectors in achieving consistent antibody priming, enhanced antibody avidity, and cytophilic isotype skew. These data strengthen the evidence that tailored combinations of vaccine platforms can achieve desired combinations of immune responses, and further encourage the co-administration of antibody-inducing recombinant protein vaccines with T cell- and antibody-inducing recombinant viral vectors as one strategy that may achieve protective blood-stage malaria immunity in humans. Copyright © 2010. Published by Elsevier Ltd.

  6. Influence of adjuvants on protection induced by a recombinant fusion protein against malarial infection.

    PubMed

    Daly, T M; Long, C A

    1996-07-01

    Previously, we described a protective immune response induced by the carboxyl-terminal region of the merozoite surface protein-1 (MSP-1) from the rodent malarial parasite Plasmodium yoelii yoelii 17XL, expressed as a fusion protein and designated glutathione S-transferase (GST)-PYC2. We also demonstrated that the humoral response induced by GST-PYC2 was the primary mechanism by which immunized animals controlled their blood-stage infections. We have now examined the influence of several adjuvants on the immune response to the GST-PYC2 fusion protein. While alum, Freund's adjuvant, Ribi adjuvant system, and TiterMax were efficacious in eliciting a protective response with GST-PYC2 in BALB/c mice, saponin failed to induce protection, although significant levels of PYC2-specific antibodies were produced in all immunized animals. This protection depended on the mouse strain since immunization of Swiss Webster mice with GST-PYC2 in alum did not produce levels of PYC2-specific antibodies comparable to those in BALB/c mice nor did it induce any demonstrable level of protection against parasite challenge. Swiss Webster mice were protected, however, when immunized with GST-PYC2 in other adjuvants. Immunization with PYC2, isolated free of GST induced lower levels of antigen-specific antibody; only those animals given PYC2 in Freund's adjuvant demonstrated a significant degree of protection, suggesting the possibility (of additional cellular effector mechanisms. These findings demonstrate that adjuvant, host genotype, and the fine specificity of the response significantly influence the protection induced by the carboxyl terminus of MSP-1 in vivo and illustrate the need to consider these factors in evaluating MSP-1 as a vaccine component.

  7. Revisiting adverse reactions to vaccines: A critical appraisal of Autoimmune Syndrome Induced by Adjuvants (ASIA).

    PubMed

    Hawkes, David; Benhamu, Joanne; Sidwell, Tom; Miles, Rhianna; Dunlop, Rachael A

    2015-05-01

    In 2011 Shoenfeld and Agmon-Levin proposed a new syndrome as a way of grouping together a range of emerging autoimmune diseases with possible adjuvant-associated causes, Autoimmune/Auto-inflammatory Syndrome Induced by Adjuvants (ASIA). At present, there is no evidence to suggest that ASIA syndrome is a viable explanation for unusual autoimmune diseases. Since the initial paper, over 80 publications have discussed ASIA. This systematic review examines the research that has been done to investigate whether ASIA is a broad umbrella term with little clinical significance, or whether there is some underlying mechanism which could be utilised to reduce the occurrence of adjuvant mediated disease. Twenty-seven animal, epidemiological and case studies were reviewed. Unfortunately, a robust animal model of ASIA using biologically relevant doses of adjuvants has yet to be defined. It is also apparent that the broadness of the current ASIA criteria lack stringency and, as a result, very few cases of autoimmune disease could be excluded from a diagnosis of ASIA. The current studies involving human cases are so diverse, in both external stimuli and in resulting conditions, that there is currently a lack of reproducible evidence for any consistent relationship between adjuvant and autoimmune condition. The addition of a mandatory criterion requiring temporal association and clinically relevant adjuvant dose would allow better definition of what constitutes a diagnosis of ASIA. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Vaccine adjuvants as potential cancer immunotherapeutics

    PubMed Central

    Temizoz, Burcu; Kuroda, Etsushi

    2016-01-01

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

  9. Inhibition of tumor-induced myeloid-derived suppressor cell function by a nanoparticulated adjuvant.

    PubMed

    Fernández, Audry; Mesa, Circe; Marigo, Ilaria; Dolcetti, Luigi; Clavell, Marilyn; Oliver, Liliana; Fernández, Luis E; Bronte, Vincenzo

    2011-01-01

    The interaction between cancer vaccine adjuvants and myeloid-derived suppressor cells (MDSCs) is currently poorly understood. Very small size proteoliposomes (VSSP) are a nanoparticulated adjuvant under investigation in clinical trials in patients with renal carcinoma, breast cancer, prostate cancer, and cervical intraepithelial neoplasia grade III. We found that VSSP adjuvant induced a significant splenomegaly due to accumulation of CD11b(+)Gr-1(+) cells. However, VSSP-derived MDSCs showed a reduced capacity to suppress both allogeneic and Ag-specific CTL response compared with that of tumor-induced MDSCs. Moreover, splenic MDSCs isolated from tumor-bearing mice treated with VSSP were phenotypically more similar to those isolated from VSSP-treated tumor-free mice and much less suppressive than tumor-induced MDSCs, both in vitro and in vivo. Furthermore, different from dendritic cell vaccination, inoculation of VSSP-based vaccine in EG.7-OVA tumor-bearing mice was sufficient to avoid tumor-induced tolerance and stimulate an immune response against OVA Ag, similar to that observed in tumor-free mice. This effect correlated with an accelerated differentiation of MDSCs into mature APCs that was promoted by VSSP. VSSP used as a cancer vaccine adjuvant might thus improve antitumor efficacy not only by stimulating a potent immune response against tumor Ags but also by reducing tumor-induced immunosuppression.

  10. Assessment of the densities of local anesthetics and their combination with adjuvants: an experimental study.

    PubMed

    Imbelloni, Luiz Eduardo; Moreira, Adriano Dias; Gaspar, Flávia Cunha; Gouveia, Marildo A; Cordeiro, José Antônio

    2009-01-01

    The relative density of a local anesthetic in relation to that of the cerebrospinal fluid (CSF) at 37 degrees C is one of the most important physical properties that affect the level of analgesia obtained after the subarachnoid administration of the drug. The objective of this study was to determine the density of local anesthetic solutions, with and without glucose, and the combination of the local anesthetic with adjuvants at 20 degrees C, 25 degrees C, and 37 degrees C. The density (g.mL(-1)) was determined by using a DMA 450 densimeter with a sensitivity of +/- 0.00001 g.mL(-1). The densities, and variations, according to the temperature were obtained for all local anesthetics and their combination with opioids at 20 degrees C, 25 degrees C, and 37 degrees C. The solution is hyperbaric if its density exceeds 1.00099, hypobaric when its density is lower than 1.00019, and isobaric when its density is greater than 1.00019 and lower than 1.00099. The densities of both local anesthetics and adjuvants decrease with the increase in temperature. At 37 degrees C, all glucose-containing solutions are hyperbaric. In the absence of glucose, all solutions are hypobaric. At 37 degrees C, morphine, fentanyl, sufentanil, and clonidine are hypobaric. The densities of local anesthetics and adjuvants decrease with the increase in temperature and increase when glucose is added. The knowledge of the relative density helps select the most adequate local anesthetic to be administered in the subarachnoid space.

  11. A nontoxic chimeric enterotoxin adjuvant induces protective immunity in both mucosal and systemic compartments with reduced IgE antibodies.

    PubMed

    Kweon, Mi-Na; Yamamoto, Masafumi; Watanabe, Fumiko; Tamura, Shinichi; Van Ginkel, Frederik W; Miyauchi, Akira; Takagi, Hiroaki; Takeda, Yoshifumi; Hamabata, Takashi; Fujihashi, Kohtaro; McGhee, Jerry R; Kiyono, Hiroshi

    2002-11-01

    A novel nontoxic form of chimeric mucosal adjuvant that combines the A subunit of mutant cholera toxin E112K with the pentameric B subunit of heat-labile enterotoxin from enterotoxigenic Escherichia coli was constructed by use of the Brevibacillus choshinensis expression system (mCTA/LTB). Nasal immunization of mice with tetanus toxoid (TT) plus mCTA/LTB elicited significant TT-specific immunoglobulin A responses in mucosal compartments and induced high serum immunoglobulin G and immunoglobulin A anti-TT antibody responses. Although TT plus native CT induced high total and TT-specific immunoglobulin E responses, use of the chimera molecule as mucosal adjuvant did not. Furthermore, all mice immunized with TT plus mCTA/LTB were protected from lethal systemic challenge with tetanus toxin. Importantly, the mice were completely protected from influenza virus infection after nasal immunization with inactivated influenza vaccine together with mCTA/LTB. These results show that B. choshinensis-derived mCTA/LTB is an effective and safe mucosal adjuvant for the induction of protective immunity against potent bacterial exotoxin and influenza virus infection.

  12. Postoperative adjuvant combination therapy with doxorubicin and noncytotoxic suramin in dogs with appendicular osteosarcoma.

    PubMed

    Alvarez, Francisco J; Kisseberth, William; Hosoya, Kenji; Lara-Garcia, Ana; Kosarek, Carrie; Murahari, Sridhar; Au, Jessie L-S; Wientjes, M Guillaume; Couto, Jason; Couto, Guillermo

    2014-01-01

    Although conventional treatment of dogs with osteosarcoma (OSA) by amputation and chemotherapy results in reported survival times (STs) of 262-413 days, no major improvements in STs have occurred in the past 2 decades. Suramin is a polysulfonated napthylurea, which at noncytotoxic concentrations in vitro, increases tumor sensitivity to chemotherapy, including doxorubicin. The study authors evaluated the combination of noncytotoxic suramin and doxorubicin after amputation in dogs with OSA. The hypothesis was that treatment of dogs with appendicular OSA with amputation, adjuvant doxorubicin, and noncytotoxic suramin would be well tolerated and result in STs at least comparable to those of doxorubicin alone. Forty-seven dogs received 6.75 mg/kg of suramin IV followed by 30 mg/m(2) of doxorubicin IV 4 hr later. Treatment was repeated q 2 wk for five doses. The median disease free time (DFI) was 203 days (range, 42-1,580+ days) and the median ST for all dogs was 369 days (range, 92-1,616+ days). There was no statistical difference in ST and DFI between greyhounds and nonngreyhounds. Adjuvant doxorubicin and noncytotoxic suramin was well tolerated in dogs with OSA following amputation. Additional studies are needed to determine if this combination treatment protocol provides additional clinical benefit compared with doxorubicin alone.

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

    PubMed

    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.

  14. Arthritis induced by adjuvant in spontaneously hypertensive and normotensive rats: endogenous glucocorticoid effects on inflammatory response.

    PubMed

    Torres, Micheli G; Kwasniewski, Fabio H; Scaliante, Luís G; Ishii-Iwamoto, Emy L; Caparroz-Assef, Silvana M; Cuman, Roberto K N; Bersani-Amado, Ciomar A

    2009-02-01

    The present study investigated arthritis induced by complete Freund adjuvant (AIA) in spontaneously hypertensive and normotensive rats (respectively, SHR and NTR rats). The inflammatory reaction was studied for 28 days by evaluating paw edema and secondary lesions found 10 days after complete Freund adjuvant (CFA) administration. The body weight of the animals and macroscopic alterations of several organs, including spleen, thymus, adrenal glands, and lymph nodes, were also analyzed. The results showed that the AIA manifestations were decreased in SHRs compared with NTRs. Moreover, this altered inflammatory response was not modified by surgical adrenalectomy.

  15. Cooperative effects of immune enhancer TPPPS and different adjuvants on antibody responses induced by recombinant ALV-J gp85 subunit vaccines in SPF chickens.

    PubMed

    Li, Yang; Meng, Fanfeng; Cui, Shuai; Fu, Jiayuan; Wang, Yixin; Cui, Zhizhong; Chang, Shuang; Zhao, Peng

    2017-03-14

    To explore the antibody responses and protective effects induced by subgroup J avian leukosis virus (ALV-J) gp85 protein vaccine plus different adjuvants (CpG and white oil adjuvant YF01) combined with the immune enhancer Taishan Pinus massoniana pollen polysaccharide (TPPPS), we immunized SPF chickens with the recombinant ALV-J gp85 protein, along with different adjuvants and immune enhancer, which protected the chickens by inducing different levels of protective antibodies. Results showed that a single injection of gp85 recombinant protein could only produce low-titre antibodies that were maintained over a short time in few chickens. When combined with YF01 or CpG adjuvants, the recombinant protein could induce high-titre antibodies in most of the immunized chickens. Moreover, when the immune enhancer TPPPS was used with the two adjuvants, it further elevated the antibody levels for a longer duration. The eggs from four groups with the highest levels of ALV-J antibodies were collected, hatched, and examined for maternal antibodies. The protection by the maternal antibodies against ALV-J infection in the TPPPS-immunized group was higher than that in the group without TPPPS, which was consistent with the observations in the parents. This study shows that the immune enhancer TPPPS, combined with YF01 or CpG adjuvants, can enhance the immunogenicity of gp85 recombinant proteins, and provide a better immuno-protection. It provides a powerful experimental basis for the development of ALV-J subunit vaccine. Efficient subunit vaccine development will also accelerate the process of purification of ALV-J.

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

    PubMed

    Rzodkiewicz, Przemysław; Gąsińska, Emilia; Gajewski, Michał; Bujalska-Zadrożny, Magdalena; Szukiewicz, Dariusz; Maśliński, Sławomir

    2016-01-01

    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. 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 21(st) 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. 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). 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 drug candidate for patients with rheumatoid arthritis.

  17. Brucella spp. lumazine synthase: a novel adjuvant and antigen delivery system to effectively induce oral immunity.

    PubMed

    Rosas, Gabriela; Fragoso, Gladis; Ainciart, Natalia; Esquivel-Guadarrama, Fernando; Santana, Angélica; Bobes, Raúl J; Ramírez-Pliego, Oscar; Toledo, Andrea; Cruz-Revilla, Carmen; Meneses, Gabriela; Berguer, Paula; Goldbaum, Fernando A; Sciutto, Edda

    2006-04-01

    Brucella lumazine synthase (BLS) has been previously used with success as a delivery system for systemic immunization against murine cysticercosis. We herein determined the usefulness of BLS as a new antigen-delivery system and mucosal-adjuvant using KETc1, one of the peptides of the anti-cysticercosis vaccine. A protection of up to 98% was induced when KETc1 was used as a chimera fused to BLS. Used as adjuvant of KETc1, BLS also induced a high level of protection (79%), which did not significantly differ from that induced by the cholera toxin (74%). KETc1 and BLS administered separately also reduced the parasite load. KETc1 administered orally as a chimera, and to a lesser extent with BLS as adjuvant, elicited IgG and IgA specific antibodies, which were detectable both in fecal extracts and in sera, and increased B and CD4 activated cells. BLS-KETc1 also increased the levels of transcription of TNF-alpha, IL-2 and IFNgamma in Peyer's patches, and in spleen, only increased TNF-alpha was observed. Overall, these results showed that BLS can be used as both an antigen-carrier and as an adjuvant in the design of new oral subunit vaccines.

  18. Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria.

    PubMed

    Alijotas-Reig, J

    2015-09-01

    In 1964, Miyoshi reported a series of patients with diverse symptoms after receiving treatment with silicone or paraffin fillers. Miyoshi named this condition 'human adjuvant disease'. Since then, the literature has been flooded with case reports and case series of granulomatous and systemic autoimmune disorders related to vaccines, infection or other adjuvants such as silicone and other biomaterials. A new term -autoimmune/inflammatory syndrome induced by adjuvants--has recently been coined for a process that includes several clinical features previously described by Miyoshi plus other clinical and laboratory parameters related to exposure to diverse external stimuli. Disorders such as siliconosis, Gulf War syndrome, macrophagic myofasciitis syndrome, sick building syndrome and post-vaccination syndrome have been included in autoimmune/inflammatory syndrome induced by adjuvants. Disorders such as Spanish toxic oil syndrome and Ardystil syndrome could also be included. Furthermore, biomaterials other than silicone should also be considered as triggering factors for these adjuvant-related syndromes. New diagnostic criteria in this field have been proposed. Nevertheless, many of these criteria are too subjective, leading to some patients being diagnosed with chronic fatigue syndrome or other 'central sensitization syndromes'. Diagnostic criteria based only on objective clinical and laboratory data to be further discussed and validated are proposed herein.

  19. Maximal adjuvant activity of nasally delivered IL-1α requires adjuvant responsive CD11c+ cells and does not correlate with adjuvant-induced in vivo cytokine production1

    PubMed Central

    Thompson, Afton L.; Johnson, Brandi T.; Sempowski, Gregory D.; Gunn, Michael D.; Hou, Baidong; DeFranco, Anthony L.; Staats, Herman F.

    2012-01-01

    IL-1 has been shown to have strong mucosal adjuvant activities, but little is known about its mechanism of action. We vaccinated IL-1R1 bone marrow chimeric mice to determine if IL-1R1 expression on stromal cells or hematopoietic cells was sufficient for the maximal adjuvant activity of nasally delivered IL-1α as determined by the acute induction of cytokine responses and induction of Bacillus anthracis lethal factor (LF)-specific adaptive immunity. Cytokine and chemokine responses induced by vaccination with IL-1α were predominantly derived from the stromal cell compartment and included G-CSF, IL-6, IL-13, MCP-1, and KC. Nasal vaccination of Il1r1−/− mice given wild-type bone marrow (WT→KO) and WT→WT mice with LF + IL-1α induced maximal adaptive immune responses, while vaccination of wild-type mice given Il1r1−/− bone marrow (KO→WT) resulted in significantly decreased production of LF-specific serum IgG, IgG subclasses, lethal toxin-neutralizing antibodies, and mucosal IgA compared to WT→KO and WT→WT mice (p < 0.05). IL-1α adjuvant activity was not dependent upon mast cells. However, the ability of IL-1α to induce serum LF-specific IgG2c and lethal toxin-neutralizing antibodies was significantly impaired in CD11c-Myd88−/− mice when compared to WT mice (p < 0.05). Our results suggest that CD11c+ cells must be directly activated by nasally administered IL-1α for maximal adjuvant activity and that, while stromal cells are required for maximal adjuvant-induced cytokine production, the adjuvant-induced stromal cell cytokine responses are not required for effective induction of adaptive immunity. PMID:22345651

  20. Evaluation of hyaluronic acid-based combination adjuvant containing monophosphoryl lipid A and aluminum salt for hepatitis B vaccine.

    PubMed

    Moon, Se-hee; Shin, Eui-Cheol; Noh, Young-Woock; Lim, Yong Taik

    2015-09-11

    Here, monophosphoryl lipid A (MPLA) and aluminum salt (Alum) were introduced into a hyaluronic acid (HA)-based combination vaccine adjuvant for hepatitis B vaccine (HBV). Although Alum is a well-known hepatitis B vaccine adjuvant that induces an enhanced humoral immune response, it cannot induce the cellular immune responses. On the other hand, MPLA has been generally reported to promote IFN-γ production via antigen-specific CD4(+) T cells, but it is not water soluble as a result of its long hydrophobic alkyl chains. To this end, water insoluble MPLA could be solubilized in an aqueous solution with the help of HA, which contains many carboxyl and hydroxyl groups that can be used to attach to the hydroxyl head groups of MPLA via hydrogen bonds. Three groups of mice were treated with either hepatitis B surface antigen (HBsAg) alone, HBsAg_Alum complex, or HBsAg_Alum_MPLA/HA complex. The group immunized with the HBsAg_Alum_MPLA/HA complex exhibited a high increase in cellular immune response as well as in humoral immune response relative to the other two groups. The antibody, cytokine and T cell levels were most elevated in the group of mice immunized with HBsAg_Alum_MPLA/HA complex, even at a 1μg/mice dose, and the magnitude was still maintained even after 8 weeks. Specifically, the antibody value was 120 times larger in mice vaccinated with HBsAg_Alum_MPLA/HA complex than in mice vaccinated with HBsAg_Alum complex designed similar to commercially available hepatitis B vaccine, Engerix B. The cytokine and T cell proliferation levels were 2 times and 6 times larger in mice adjuvanted with HBsAg_Alum_MPLA/HA complex than in those vaccinated with HBsAg_Alum. The results therefore indicate that incorporating MPLA and Alum with HA can be a potent strategy to increase both the magnitude and the persistence of HBsAg-specific immune responses to protect hosts against hepatitis B virus infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. T Helper 1–Inducing Adjuvant Protects against Experimental Paracoccidioidomycosis

    PubMed Central

    de Oliveira, Leandro Licursi; Coltri, Kely Cristine; Cardoso, Cristina Ribeiro Barros; Roque-Barreira, Maria-Cristina; Panunto-Castelo, Ademilson

    2008-01-01

    Immunostimulatory therapy is a promising approach to improving the treatment of systemic fungal infections such as paracoccidioidomycosis (PCM), whose drug therapy is usually prolonged and associated with toxic side effects and relapses. The current study was undertaken to determine if the injection of a T helper (Th) 1–stimulating adjuvant in P. brasiliensis–infected mice could have a beneficial effect on the course of experimental PCM. For this purpose, mice were infected and treated with complete Freund's adjuvant (CFA), a well-established Th1 experimental inductor, or incomplete Freund's adjuvant (IFA - control group) on day 20 postinfection. Four weeks after treatment, the CFA-treated mice presented a mild infection in the lungs characterized by absence of epithelioid cell granulomas and yeast cells, whereas the control mice presented multiple sites of focal epithelioid granulomas with lymphomonocytic halos circumscribing a high number of viable and nonviable yeast cells. In addition, CFA administration induced a 2.4 log reduction (>99%) in the fungal burden when compared to the control group, and led to an improvement of immune response, reversing the immunosuppression observed in the control group. The immunotherapy with Th1-inducing adjuvant, approved to be used in humans, might be a valuable tool in the treatment of PCM and potentially useful to improve the clinical cure rate in humans. PMID:18335066

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

    PubMed Central

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

    2014-01-01

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

  3. Vaccination of dogs with six different candidate leishmaniasis vaccines composed of a chimerical recombinant protein containing ribosomal and histone protein epitopes in combination with different adjuvants.

    PubMed

    Poot, J; Janssen, L H M; van Kasteren-Westerneng, T J; van der Heijden-Liefkens, K H A; Schijns, V E J C; Heckeroth, A

    2009-07-16

    Chimerical protein "Q", composed of antigenic ribosomal and histone sequences, in combination with live BCG is a promising canine leishmaniasis vaccine candidate; one of the few vaccine candidates that have been tested successfully in dogs. Unfortunately, live BCG is not an appropriate adjuvant for commercial application due to safety problems in dogs. In order to find a safe adjuvant with similar efficacy to live BCG, muramyl dipeptide, aluminium hydroxide, Matrix C and killed Propionibacterium acnes in combination with either E. coli- or baculovirus-produced recombinant JPCM5_Q protein were tested. Groups of five or seven dogs were vaccinated with six different adjuvant-antigen combinations and challenged with a high dose intravenous injection of Leishmania infantum JPC strain promastigotes. All candidate vaccines proved to be safe, and both humoral and cellular responses to the recombinant proteins were detected at the end of the prime-boost vaccination scheme. However, clinical and parasitological data obtained during the 10 month follow-up period indicated that protection was not induced by either of the six candidate vaccines. Although no direct evidence was obtained, our data suggest that live BCG may have a significant protective effect against challenge with L. infantum in dogs.

  4. Chimeric cytotoxin IL2-PE40 delays and mitigates adjuvant-induced arthritis in rats.

    PubMed Central

    Case, J P; Lorberboum-Galski, H; Lafyatis, R; FitzGerald, D; Wilder, R L; Pastan, I

    1989-01-01

    Adjuvant arthritis in rats is a T-cell dependent "autoimmune" disease with close similarities to several forms of human arthritis. Injection of mycobacterial adjuvant leads to T-cell activation and proliferation, processes in which the de novo expression of the interleukin 2 (IL-2) receptor plays a pivotal role. The subsequent massive mononuclear cell infiltration of the joints ultimately results in complete joint destruction. Because activation of the helper/inducer subset of T lymphocytes is critical to the establishment of disease, we reasoned that IL2-PE40, a cytotoxic IL-2-Pseudomonas exotoxin fusion protein that targets the membrane-penetration and ADP-ribosylation domains of the toxin to cells bearing the IL-2 receptor, would be an effective and specific therapy. Adjuvant-injected rats were randomized to treatment with IL2-PE40, phosphate-buffered saline, or either of two control proteins related to IL2-PE40 but lacking either the receptor-binding moiety or an enzymatically active toxin domain and previously demonstrated to lack cytotoxicity in vitro. Intraperitoneal IL2-PE40 given before the establishment of overt clinical disease proved an effective and specific modifier of adjuvant arthritis by clinical, histological, and radiographic criteria. Our data suggest that IL2-PE40 may be effective in those diseases in which activated T-cells play an important role. Images PMID:2492102

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Matsuura, Wataru; Harada, Shinichi; Tokuyama, Shogo

    2016-01-01

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

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

    PubMed Central

    Gąsińska, Emilia; Gajewski, Michał; Bujalska-Zadrożny, Magdalena; Szukiewicz, Dariusz; Maśliński, Sławomir

    2016-01-01

    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 drug candidate for

  9. Characterisation of local immune responses induced by a novel nano-particle based carrier-adjuvant in sheep.

    PubMed

    Gamvrellis, Anita; Gloster, Simone; Jefferies, Meryem; Mottram, Patricia L; Smooker, Peter; Plebanski, Magdalena; Scheerlinck, Jean-Pierre Y

    2013-09-01

    Most adjuvants require danger signals to promote immune responses against vaccine antigens. Our previous studies have characterised a powerful nano-particulate antigen delivery system, which by itself does not induce inflammation, and which further appears to induce substantial immune responses in mice and sheep without the requirement for added stimulators of toll like receptors or other pathogen recognition receptors. In the present study we dissect the nature of the early induction phase of the immune response stimulated by such a vaccine comprising 40 nm polystyrene nano-particles conjugated to the antigen. We analyse the kinetics of export from an individual draining lymph node from the sheep, of antibodies and cytokines as well as antigen responsive CD4 and CD8 T cells. Our results indicate that simple inert nano-bead based antigen delivery into the draining area of the lymph node is highly efficient at priming combined humoral and T cell antigen specific immunity without the need for added 'danger signals'. Furthermore this nano-bead adjuvant is a potent agent capable of promoting cross-priming for CD8 T cell induction in sheep. Interestingly, using nano-beads, similarly to what has been observed with natural pathogen based lymph node stimulation, a phase of CD4 T cell priming and export preceded CD8 T cell induction, suggesting the engagement of natural priming processes and kinetics. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Role of phyto-stabilised silver nanoparticles in suppressing adjuvant induced arthritis in rats.

    PubMed

    Mani, Aparna; Vasanthi, C; Gopal, V; Chellathai, Darling

    2016-12-01

    The present study was aimed to evaluate the anti-arthritic effects of silver nanoparticles synthesised using Piper nigrum extract and to further establish its mechanism of action in a rat model of adjuvant induced arthritis (AA). Adjuvant arthritis was induced by injecting complete Freund's adjuvant (0.1mL) into the left hind paw of 36 albino Wistar rats (n=6). Silver nanoparticles stabilised with Piper nigrum extract (25 and 50mg/kg). Commercial silver nanoparticles (50mg/kg) and methotrexate (0.1mg/kg) were administered by intraperitoneal route from day 11 to day 22 on alternate days. It was found that treatment with silver nanoparticles stabilised with Piper nigrum (S-AgNPs) significantly reduced the paw edema and alleviated the histopathological changes of cell infiltration, synovial hyperplasia, bone and cartilage destruction. Furthermore, the phytostabilised silver nanoparticles (S-AgNPs) inhibited the protein expression of NF-kβ p65 and TNF-α as evidenced by immunohistochemistry analysis. Our current findings suggest that silver nanoparticles stabilised with Piper nigrum extract (S-AgNPs) have potent anti-arthritic activity which is mediated by inhibition of TNF-α and suppression of pro-inflammatory cytokines that are secreted in response to activated transcription factors of NF-kβ. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Autoimmune syndrome induced by adjuvants (ASIA) in the Middle East: morphea following silicone implantation.

    PubMed

    Kivity, S; Katz, M; Langevitz, P; Eshed, I; Olchovski, D; Barzilai, A

    2012-02-01

    Morphea and other scleroderma-like skin conditions are occasionally linked with exposure to chemical compounds such as silicone. We treated a 56-year-old woman with generalized severe skin induration accompanied with systemic symptoms and peripheral eosinophilia, which appeared 2.5 years after breast silicone implantation and abdominal liposuction. Blood test results and histopathological examination of her skin suggested the diagnosis of morphea overlapping with eosinophilic fasciitis. Her skin disease was presumed to be an autoimmune reaction to silicone implantation. While the removal of the implants did not improve her illness, treatment with 1 mg/kg prednisone and PUVA bath was initiated, with some improvement. This patient illustrates an example of ASIA (Autoimmune Syndrome Induced by Adjuvants), as her disease appeared following exposure to an adjuvant stimulus, with 'typical', although not well-defined, autoimmune manifestations.

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

    PubMed

    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.

  13. Adjuvanted inactivated influenza A(H3N2) vaccines induce stronger immunogenicity in mice and confer higher protection in ferrets than unadjuvanted inactivated vaccines.

    PubMed

    Ann, Julie; Samant, Mukesh; Rheaume, Chantal; Dumas, Carole; Beaulieu, Edith; Morasse, Audrey; Mallett, Corey; Hamelin, Marie-Eve; Papadopoulou, Barbara; Boivin, Guy

    2014-09-29

    Influenza viruses are major respiratory pathogens and the development of improved vaccines to prevent these infections is of high priority. Here, we evaluated split inactivated A(H3N2) vaccines (A/Uruguay/716/2007) combined or not with adjuvants (AS03, AS25 and Protollin) and administered by three different routes, intramuscular (i.m.), intranasal (i.n.) or intradermal (i.d.), both in BALB/c mice and in ferrets. Ferrets were challenged with the homologous strain A/Uruguay/716/2007 (H3N2) or the heterologous strain A/Perth/16/2009 (H3N2) 4 weeks after the second immunization with A/Uruguay/716/2007 vaccines. Temperature, weight loss and clinical signs were monitored on a daily basis and nasal washes were performed to evaluate viral titers in the upper respiratory tract. All adjuvanted vaccines induced stronger humoral immune responses than unadjuvanted ones in both mice and ferrets. In mice, the AS03- and AS25-adjuvanted i.m. vaccines generated a mixed Th1-Th2 response at 6 and 19 weeks after the last immunization as shown by the production of IgG1 and IgG2a antibodies as well as the production of IL-2, IL-4 and IFN-γ by CD4+ and CD8+ T cells. HAI and MN titers were also higher in those groups when compared to the i.n. Protollin-adjuvanted and unadjuvanted groups. The Protollin-adjuvanted i.n. vaccine induced a more Th1 oriented response with a significant production of IgA in bronchoalveolar lavages. In ferrets, the AS03- and AS25-adjuvanted i.m. vaccines also induced higher HAI and MN titers compared to the other groups. These vaccines also significantly decreased viral titers after challenge with both the homologous A/Uruguay/716/2007 (H3N2) and the heterologous A/Perth/16/2009 (H3N2) strains. In conclusion, adjuvanted influenza vaccines elicited stronger humoral response in mice and conferred greater protection in naive ferrets than unadjuvanted ones. Interestingly, the AS25 adjuvant system containing monophosphoryl-lipid-A appears particularly promising for

  14. Adjuvants for Animal Vaccines.

    PubMed

    Burakova, Yulia; Madera, Rachel; McVey, Scott; Schlup, John R; Shi, Jishu

    2017-06-15

    Vaccines are essential tools for the prevention and control of infectious diseases in animals. One of the most important steps in vaccine development is the selection of a suitable adjuvant. The focus of this review is the adjuvants used in vaccines for animals. We will discuss current commercial adjuvants and experimental formulations with attention to mineral salts, emulsions, bacterial-derived components, saponins, and several other immunoactive compounds. In addition, we will also examine the mechanisms of action for different adjuvants, examples of adjuvant combinations in one vaccine formulation, and challenges in the research and development of veterinary vaccine adjuvants.

  15. Rotavirus capsid VP6 protein acts as an adjuvant in vivo for norovirus virus-like particles in a combination vaccine

    PubMed Central

    Blazevic, Vesna; Malm, Maria; Arinobu, Daisuke; Lappalainen, Suvi; Vesikari, Timo

    2016-01-01

    ABSTRACT Rotavirus (RV) and norovirus (NoV) are the 2 leading causes of acute viral gastroenteritis worldwide. We have developed a non-live NoV and RV vaccine candidate consisting of NoV virus-like particles (VLPs) and recombinant polymeric RV VP6 protein produced in baculovirus-insect cell expression system. Both components have been shown to induce strong potentially protective immune responses. As VP6 nanotubes are highly immunogenic, we investigated here a possible adjuvant effect of these structures on NoV-specific immune responses in vivo. BALB/c mice were immunized intramuscularly with a suboptimal dose (0.3 μg) of GII.4 or GI.3 VLPs either alone or in a combination with 10 μg dose of VP6 and induction of NoV-specific antibodies in sera of experimental animals were measured. Blocking assay using human saliva or synthetic histo-blood group antigens was employed to test NoV blocking antibodies. Suboptimal doses of the VLPs alone did not induce substantial anti-NoV antibodies. When co-administered with the VP6, considerable titers of not only type-specific but also cross-reactive IgG antibodies against NoV VLP genotypes not included in the vaccine composition were induced. Most importantly, NoV-specific blocking antibodies, a surrogate for neutralizing antibodies, were generated. Our results show that RV VP6 protein has an in vivo adjuvant effect on NoV-specific antibody responses and support the use of VP6 protein as a part of the NoV-RV combination vaccine, especially when addition of external adjuvants is not desirable. PMID:26467630

  16. Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)--animal models as a proof of concept.

    PubMed

    Cruz-Tapias, Paola; Agmon-Levin, Nancy; Israeli, Eitan; Anaya, Juan-Manuel; Shoenfeld, Yehuda

    2013-01-01

    ASIA syndrome, "Autoimmune (Auto-inflammatory) Syndromes Induced by Adjuvants" includes at least four conditions which share a similar complex of signs and symptoms and have been defined by hyperactive immune responses: siliconosis, macrophagic myofasciitis syndrome, Gulf war syndrome and post-vaccination phenomena. Exposure to adjuvants has been documented in these four medical conditions, suggesting that the common denominator to these syndromes is a trigger entailing adjuvant activity. An important role of animal models in proving the ASIA concept has been established. Experimentally animal models of autoimmune diseases induced by adjuvants are currently widely used to understand the mechanisms and etiology and pathogenesis of these diseases and might thus promote the development of new diagnostic, predictive and therapeutic methods. In the current review we wish to unveil the variety of ASIA animal models associated with systemic and organ specific autoimmune diseases induced by adjuvants. We included in this review animal models for rheumatoid arthritis-like disease, for systemic lupus erythematosus-like disease, autoimmune thyroid disease-like disease, antiphospholipid syndrome, myocarditis and others. All these models support the concept of ASIA, as the Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants.

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

    PubMed Central

    2014-01-01

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

  18. Inducing Dose Sparing with Inactivated Polio Virus Formulated in Adjuvant CAF01

    PubMed Central

    Dietrich, Jes; Andreasen, Lars Vibe; Andersen, Peter; Agger, Else Marie

    2014-01-01

    The development of new low cost inactivated polio virus based vaccines (IPV) is a high priority, and will be required to eradicate polio. In addition, such a vaccine constitutes the only realistic polio vaccine in the post-eradication era. One way to reduce the cost of a vaccine is to increase immunogenicity by use of adjuvants. The CAF01 adjuvant has previously been shown to be a safe and potent adjuvant with several antigens, and here we show that in mice IPV formulated with CAF01 induced increased systemic protective immunity measured by binding and neutralization antibody titers in serum. CAF01 also influenced the kinetics of both the cellular and humoral response against IPV to produce a faster, as well as a stronger, response, dominated by IgG2a, IgG2b, and IgG2c isotypes as well as IPV specific T cells secreting IFN-γ/IL-2. Finally, as intestinal immunity is also a priority of polio vaccines, we present a vaccine strategy based on simultaneous priming at an intradermal and an intramuscular site that generate intestinal immune responses against polio virus. Taken together, the IPV-CAF01 formulation constitutes a new promising vaccine against polio with the ability to generate strong humoral and cellular immunity against the polio virus. PMID:24956110

  19. Inducing dose sparing with inactivated polio virus formulated in adjuvant CAF01.

    PubMed

    Dietrich, Jes; Andreasen, Lars Vibe; Andersen, Peter; Agger, Else Marie

    2014-01-01

    The development of new low cost inactivated polio virus based vaccines (IPV) is a high priority, and will be required to eradicate polio. In addition, such a vaccine constitutes the only realistic polio vaccine in the post-eradication era. One way to reduce the cost of a vaccine is to increase immunogenicity by use of adjuvants. The CAF01 adjuvant has previously been shown to be a safe and potent adjuvant with several antigens, and here we show that in mice IPV formulated with CAF01 induced increased systemic protective immunity measured by binding and neutralization antibody titers in serum. CAF01 also influenced the kinetics of both the cellular and humoral response against IPV to produce a faster, as well as a stronger, response, dominated by IgG2a, IgG2b, and IgG2c isotypes as well as IPV specific T cells secreting IFN-γ/IL-2. Finally, as intestinal immunity is also a priority of polio vaccines, we present a vaccine strategy based on simultaneous priming at an intradermal and an intramuscular site that generate intestinal immune responses against polio virus. Taken together, the IPV-CAF01 formulation constitutes a new promising vaccine against polio with the ability to generate strong humoral and cellular immunity against the polio virus.

  20. Vaccination with Clostridium perfringens recombinant proteins in combination with Montanide™ ISA 71 VG adjuvant increases protection against experimental necrotic enteritis in commercial broiler chickens.

    PubMed

    Jang, Seung I; Lillehoj, Hyun S; Lee, Sung-Hyen; Lee, Kyung Woo; Lillehoj, Erik P; Hong, Yeong Ho; An, Dong-Jun; Jeong, Wooseog; Chun, Ji-Eun; Bertrand, François; Dupuis, Laurent; Deville, Sébastien; Arous, Juliette Ben

    2012-08-03

    This study was performed to compare four Clostridium perfringens recombinant proteins as vaccine candidates using the Montanide™ ISA 71 VG adjuvant in an experimental model of necrotic enteritis. Broiler chickens were immunized subcutaneously with purified clostridial recombinant NetB toxin, pyruvate: ferredoxin oxidoreductase (PFO), α-toxin, or elongation factor-Tu (EF-Tu), or with vehicle control, in conjunction with ISA 71 VG, and intestinal lesion scores, body weight gains, NetB toxin and PFO antibody levels, and proinflammatory cytokine and chemokine levels were measured as outcomes of protection following oral co-infection with C. perfringens and Eimeria maxima. Birds immunized with all recombinant proteins plus ISA 71 VG showed significantly reduced gut lesions compared with the ISA 71 VG-only group. Birds immunized with NetB toxin or PFO plus ISA 71 VG exhibited significantly increased body weight gains compared with the ISA 71 VG alone group. Greater NetB toxin antibody titers were observed in the NetB/ISA 71 VG group, and greater PFO antibody titers were evident in the PFO/ISA 71 VG group, each compared with the other three vaccine/adjuvant groups. Finally, decreased levels of gene transcripts encoding interleukin-8, tumor necrosis factor superfamily 15, and LPS-induced TNF-α factor were observed in the intestinal lymphocytes of chickens immunized with NetB toxin, PFO, α-toxin, and/or EF-Tu in the presence of ISA 71 VG compared with ISA 71 VG alone. All parameters evaluated were equal in co-infected chickens given ISA 71 VG alone compared with infected/adjuvant-free birds, indicating that the adjuvant itself did not have a disease protective effect. These results suggest that vaccination with clostridial recombinant proteins, particularly NetB toxin or PFO, in combination with ISA 71 VG enhances protective immunity against experimental necrotic enteritis in broiler chickens. Published by Elsevier Ltd.

  1. Live birth rates after combined adjuvant therapy in IVF-ICSI cycles: a matched case-control study.

    PubMed

    Motteram, C; Vollenhoven, B; Hope, N; Osianlis, T; Rombauts, L J

    2015-04-01

    The effectiveness of combined co-treatment with aspirin, doxycycline, prednisolone, with or without oestradiol patches, was investigated on live birth (LBR) rates after fresh and frozen embryo transfers (FET) in IVF and intracytoplasmic sperm injection cycles. Cases (n = 485) and controls (n = 485) were extensively matched in a one-to-one ratio on nine physical and clinical parameters: maternal age, body mass index, smoking status, stimulation cycle number, cumulative dose of FSH, stimulation protocol, insemination method, day of embryo transfer and number of embryos transferred. No significant differences were found in fresh cycles between cases and controls for the pregnancy outcomes analysed, but fewer surplus embryos were available for freezing in the combined adjuvant group. In FET cycles, LBR was lower in the treatment group (OR: 0.49, 95% CI 0.25 to 0.95). The lower LBR in FET cycles seemed to be clustered in patients receiving combined adjuvant treatment without luteal oestradiol (OR 0.37, 95% CI 0.17 to 0.80). No difference was found in LBR between cases and controls when stratified according to the number of previous cycles (<3 or ≥3). There is no benefit of this combined adjuvant strategy in fresh IVF cycles, and possible harm when used in frozen cycles.

  2. Anti-Arthritic Activity of Premna serratifolia Linn., Wood against Adjuvant Induced Arthritis

    PubMed Central

    Rajendran, Rekha; Krishnakumar, Ekambaram

    2010-01-01

    Adjuvant induced arthritis is a chronic crippling, skeleton-muscular disorder having nearest approximation to human rheumatoid arthritis for which there is currently no medicine available effecting a permanent cure. Even modern drugs used for the amelioration of the symptoms, offer only temporary relief and also produce severe side effects. In the indigenous system of medicine, wood of Premna serratifolia Linn., is reported to be useful in the treatment of arthritis. It is a large shrub, distributed throughout Asia, used against a wide variety of diseases. However, no systematic study has been reported regarding its anti-arthritic activity. This work was aimed at the scientific validation of the ethno-pharmacological claim about its anti-arthritic property. In the present study, anti-arthritic activity of ethanol extract of Premna serratifolia Linn., wood is done by Freund's adjuvant induced arthritis model. Loss in body weight during arthritis condition was corrected on treatment with ethanol extract and standard drug, indomethacin. Biochemical parameters such as hemoglobin content, total WBC, RBC, erythrocyte and sedimentation rate were also estimated. The ethanol extract at the dose of 300 mg/kg body weight inhibited the rat paw edema by 68.32% which is comparable with standard drug indomethacin 74.87% inhibition of rat paw edema after 21 days. The results of the current investigation concluded, ethanol extract of Premna serratifolia Linn., wood possess a significant anti-arthritic activity against adjuvant induced arthritis and justifying its therapeutic role in arthritic condition. The observed anti-arthritic activity may be due to the presence of phytoconstituents such as irridiod glycosides, alkaloids, phenolic compounds and flavonoids. PMID:23407688

  3. Anti-Arthritic Activity of Premna serratifolia Linn., Wood against Adjuvant Induced Arthritis.

    PubMed

    Rajendran, Rekha; Krishnakumar, Ekambaram

    2010-04-01

    Adjuvant induced arthritis is a chronic crippling, skeleton-muscular disorder having nearest approximation to human rheumatoid arthritis for which there is currently no medicine available effecting a permanent cure. Even modern drugs used for the amelioration of the symptoms, offer only temporary relief and also produce severe side effects. In the indigenous system of medicine, wood of Premna serratifolia Linn., is reported to be useful in the treatment of arthritis. It is a large shrub, distributed throughout Asia, used against a wide variety of diseases. However, no systematic study has been reported regarding its anti-arthritic activity. This work was aimed at the scientific validation of the ethno-pharmacological claim about its anti-arthritic property. In the present study, anti-arthritic activity of ethanol extract of Premna serratifolia Linn., wood is done by Freund's adjuvant induced arthritis model. Loss in body weight during arthritis condition was corrected on treatment with ethanol extract and standard drug, indomethacin. Biochemical parameters such as hemoglobin content, total WBC, RBC, erythrocyte and sedimentation rate were also estimated. The ethanol extract at the dose of 300 mg/kg body weight inhibited the rat paw edema by 68.32% which is comparable with standard drug indomethacin 74.87% inhibition of rat paw edema after 21 days. The results of the current investigation concluded, ethanol extract of Premna serratifolia Linn., wood possess a significant anti-arthritic activity against adjuvant induced arthritis and justifying its therapeutic role in arthritic condition. The observed anti-arthritic activity may be due to the presence of phytoconstituents such as irridiod glycosides, alkaloids, phenolic compounds and flavonoids.

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

    PubMed

    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.

  5. Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome?

    PubMed

    Meroni, Pier Luigi

    2011-02-01

    There has been considerable interest in the role of environmental factors and the induction of autoimmunity and the ways by which they facilitate loss of tolerance. Clearly both genetic and environmental factors are incriminated, as evidenced by the lack of concordance in identical twins and the relatively recent identification of the shared epitope in rheumatoid arthritis. In this issue a new syndrome called 'Asia'-autoimmune/auto-inflammatory syndrome induced by adjuvants has been proposed. It is an intriguing issue and one that is likely to be provocative and lead to further biologic and molecular investigations.

  6. Combination of adjuvant chemotherapy and radiotherapy is associated with improved survival at early stage type II endometrial cancer and carcinosarcoma.

    PubMed

    Sozen, Hamdullah; Çiftçi, Rumeysa; Vatansever, Dogan; Topuz, Samet; Iyibozkurt, Ahmet Cem; Bozbey, Hamza Ugur; Yaşa, Cenk; Çali, Halime; Yavuz, Ekrem; Kucucuk, Seden; Aydiner, Adnan; Salihoglu, Yavuz

    2016-04-01

    The aim of this study was to describe the impact of postoperative adjuvant treatment modalities and identify risk factors associated with recurrence and survival rates in women diagnosed with early stage type II endometrial cancer and carcinosarcoma. In this retrospective study, patients diagnosed with early stage (stages I-II) carcinosarcoma and type II endometrial cancer were reviewed. All women underwent comprehensive surgical staging. Postoperative treatment options of chemotherapy (CT), radiotherapy (RT), observation (OBS) and chemotherapy-radiotherapy (CT-RT) combination were compared in terms of recurrence and survival outcome. In CT-RT treatment arm, recurrence rate was found as 12.5% and this result is significantly lower than the other treatment approaches (P = 0.01 CT alone: 33.3%, RT alone: 26.7%, OBS: 62.5%). Three-year disease free survival(DFS) rate and overall survival (OS) rate were statistically higher for the group of women treated with combination of CT-RT (92-95%) compared to the women treated with RT alone (65-72%), treated with CT alone (67-74%) and women who received no adjuvant therapy (38-45%). The multivariate analysis revealed that carcinosarcoma histology was associated with shortened DFS and OS (P = 0.001, P = 0.002). On the other hand, being at stage Ia (P = 0.01, P = 0.04) and receiving adjuvant treatment of CT-RT combination (P = 0.005, P = 0.002) appeared to lead to increased DFS and OS rates. We identified that a combination treatment of chemotherapy and radiotherapy is superior compared to other postoperative adjuvant treatment approaches concerning PFS, OS and recurrence rates in stages I-II of type II endometrial cancers and uterine carcinosarcoma. © 2016 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

  7. Phase 2 Study of Erlotinib Combined With Adjuvant Chemoradiation and Chemotherapy in Patients With Resectable Pancreatic Cancer

    SciTech Connect

    Herman, Joseph M.; Fan, Katherine Y.; Wild, Aaron T.; Hacker-Prietz, Amy; Wood, Laura D.; Blackford, Amanda L.; Ellsworth, Susannah; Zheng, Lei; Le, Dung T.; De Jesus-Acosta, Ana; Hidalgo, Manuel; Donehower, Ross C.; Schulick, Richard D.; Edil, Barish H.; Choti, Michael A.; Hruban, Ralph H.; and others

    2013-07-15

    Purpose: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC. Methods and Materials: Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m{sup 2} twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m{sup 2} on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). Results: The median follow-up time was 18.2 months (interquartile range, 13.8-27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4-17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9-29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P=.001) and OS (HR, 4.98; P=.02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P=.009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively. Conclusion: Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.

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

    PubMed

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

    2015-12-01

    Theophylline (non-specific PDE inhibitor) and their interactions with nitric oxide modulators were evaluated in adjuvant-induced arthritic model of rats. Wistar rats (200-300g), 8 animals per group were used in the study. The animals were injected with 0.1mL of squalene and 0.2mL of complete Freund's adjuvant on day (0) in sub-planter region of right hind paw controls received only saline. The treatment with theophylline and nitric oxide modulators were done from day 14 to day 28. Arthritis indexes, ankle diameter, paw volume, and body weight were determined to assess RA progression from day (0) to day 28. On day 28 animals were sacrificed and their blood collected for IL-10 and TNF-α cytokine levels and hind paw for pathological analysis. Synovial fluid from joint spaces of CFA inoculated rats was collected to estimate TNF-α level in synovial fluid. The data obtained was analyzed by two-way ANOVA followed by the Newman-Keuls post-hoc test. Theophylline (10 and 20mg/kg) significantly decreased adjuvant induced increased arthritis-index, paw volume and ankle diameter (p<0.05 in all parameters) compared to only adjuvant control group. It also reversed adjuvant induced slight decrease in body weight to normalcy. l-Arginine 100mg/kg+theophylline 20mg/kg suppressed TNF-α and elevates IL-10 level as well as reversed adjuvant-induced elevated arthritic parameters as compared to only adjuvant and prednisone group (p<0.001). Synovial TNF-α level of adjuvant only group was several fold higher than its serum level. Treatment with theophylline 20mg/kg significantly reduces synovial TNF-α level as compared to adjuvant only group. Theophylline 20mg/kg+L-NAME 10mg/kg significantly reversed these adjuvant-induced changes in immunological, histopathological and arthritis parameters (p<0.05). Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Adjuvant liposomal doxorubicin markedly affects radiofrequency (RF) ablation-induced effects on periablational microvasculature

    PubMed Central

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

    2013-01-01

    Purpose To evaluate the effects of radiofrequency (RF) ablation without and with adjuvant IV liposomal doxorubicin (Doxil®) on microvessel morphology and patency and intratumoral drug delivery and retention. Materials and Methods A total of 133 tumors/animals were used. First, single subcutaneous tumors (R3230 in Fischer rats, and 786-0 in nude mice) were randomized to receive RF alone or no treatment, and sacrificed 0-72hr post-treatment. Next, combined RF/liposomal doxorubicin (1mg given 15min post-RF) was studied in R3230 tumors at 0-72hr post-treatment. Histopathologic assessment including immunohistochemical staining for ced caspase-3), heat shock protein 70 and CD34 were performed to assess morphologic vessel appearance, vessel diameter, and microvascular density. Subsequently, animals were randomized to receive RF alone, RF/liposomal doxorubicin, or control tumors, followed by intravenous fluorescent-labeled liposomes (a surrogate marker) given 0-24hr post-RF to permit qualitative assessment. Results RF ablation alone results in enlarged and dysmorphic vessels from 0-4hr, peaking at 12-24hr post-RF, occurring preferentially closer to the electrode. The addition of doxorubicin resulted in earlier vessel contraction (mean vessel area 47539±9544μm² vs. 1854±458μm² for RF alone at 15min, p<0.05). Combined RF/liposomal doxorubicin produced similar fluorescence 1hr post-treatment (40.88±33.53 AU/μm² vs. 22.1±13.19 AU/μm², p=0.14), but significantly less fluorescence at 4hr (24.3±3.65 AU/μm² vs. 2.8 ±3.14 AU/μm², p<0.002) compared to RF alone denoting earlier reduction in microvascular patency. Conclusion RF ablation induces morphologic changes to vessels within the ablation zone lasting up to 12-24hr post-treatment. The addition liposomal doxorubicin causes early vessel contraction and a reduction in periablational microvascular patency. Such changes will likely need to be considered when determining optimal drug administration and imaging

  10. Adjuvants for malaria vaccines.

    PubMed

    Coler, R N; Carter, D; Friede, M; Reed, S G

    2009-09-01

    There is a renewed enthusiasm about subunit vaccines for malaria coincident with the formation of new alliances and partnerships raising international public awareness, attracting increased resources and the re-focusing of research programs on adjuvant development for infectious disease vaccines. It is generally accepted that subunit vaccines for malaria will require adjuvants to induce protective immune responses, and availability of suitable adjuvants has in the past been a barrier to the development of malaria vaccines. Several novel adjuvants are now in licensed products or in late stage clinical development, while several others are in the earlier development pipeline. Successful vaccine development requires knowing which adjuvants to use and knowing how to formulate adjuvants and antigens to achieve stable, safe, and immunogenic vaccines. For the majority of vaccine researchers this information is not readily available, nor is access to well-characterized adjuvants. In this minireview, we outline the current state of adjuvant research and development as it pertains to effective malaria vaccines.

  11. Gemcitabine-Based Combination Chemotherapy Followed by Radiation With Capecitabine as Adjuvant Therapy for Resected Pancreas Cancer

    SciTech Connect

    Desai, Sameer; Ben-Josef, Edgar; Griffith, Kent A.; Simeone, Diane; Greenson, Joel K.; Francis, Isaac R.; Hampton, Janet; Colletti, Lisa; Chang, Alfred E.; Lawrence, Theodore S.; Zalupski, Mark M.

    2009-12-01

    Purpose: To report outcomes for patients with resected pancreas cancer treated with an adjuvant regimen consisting of gemcitabine-based combination chemotherapy followed by capecitabine and radiation. Patients and Methods: We performed a retrospective review of a series of patients treated at a single institution with a common postoperative adjuvant program. Between January 2002 and August 2006, 43 resected pancreas cancer patients were offered treatment consisting of 4, 21-day cycles of gemcitabine 1 g/m{sup 2} intravenously over 30 min on Days 1 and 8, with either cisplatin 35 mg/m{sup 2} intravenously on Days 1 and 8 or capecitabine 1500 mg/m{sup 2} orally in divided doses on Days 1-14. After completion of combination chemotherapy, patients received a course of radiotherapy (54 Gy) with concurrent capecitabine (1330 mg/m{sup 2} orally in divided doses) day 1 to treatment completion. Results: Forty-one patients were treated. Median progression-free survival for the entire group was 21.7 months (95% confidence interval 13.9-34.5 months), and median overall survival was 45.9 months. In multivariate analysis a postoperative CA 19-9 level of >=180 U/mL predicted relapse and death. Toxicity was mild, with only two hospitalizations during adjuvant therapy. Conclusions: A postoperative adjuvant program using combination chemotherapy with gemcitabine and either cisplatin or capecitabine followed by radiotherapy with capecitabine is tolerable and efficacious and should be considered for Phase III testing in this group of patients.

  12. Cationic Lipid/DNA Complex-Adjuvanted Influenza A Virus Vaccination Induces Robust Cross-Protective Immunity▿

    PubMed Central

    Hong, David K.; Chang, Stella; Botham, Crystal M.; Giffon, Thierry D.; Fairman, Jeffery; Lewis, David B.

    2010-01-01

    Influenza A virus is a negative-strand segmented RNA virus in which antigenically distinct viral subtypes are defined by the hemagglutinin (HA) and neuraminidase (NA) major viral surface proteins. An ideal inactivated vaccine for influenza A virus would induce not only highly robust strain-specific humoral and T-cell immune responses but also cross-protective immunity in which an immune response to antigens from a particular viral subtype (e.g., H3N2) would protect against other viral subtypes (e.g., H1N1). Cross-protective immunity would help limit outbreaks from newly emerging antigenically novel strains. Here, we show in mice that the addition of cationic lipid/noncoding DNA complexes (CLDC) as adjuvant to whole inactivated influenza A virus vaccine induces significantly more robust adaptive immune responses both in quantity and quality than aluminum hydroxide (alum), which is currently the most widely used adjuvant in clinical human vaccination. CLDC-adjuvanted vaccine induced higher total influenza virus-specific IgG, particularly for the IgG2a/c subclass. Higher levels of multicytokine-producing influenza virus-specific CD4 and CD8 T cells were induced by CLDC-adjuvanted vaccine than with alum-adjuvanted vaccine. Importantly, CLDC-adjuvanted vaccine provided significant cross-protection from either a sublethal or lethal influenza A viral challenge with a different subtype than that used for vaccination. This superior cross-protection afforded by the CLDC adjuvant required CD8 T-cell recognition of viral peptides presented by classical major histocompatibility complex class I proteins. Together, these results suggest that CLDC has particular promise for vaccine strategies in which T cells play an important role and may offer new opportunities for more effective control of human influenza epidemics and pandemics by inactivated influenza virus vaccine. PMID:20943978

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

    PubMed

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

    2013-07-01

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

  14. Radiation recall dermatitis induced by tamoxifen during adjuvant breast cancer treatment

    PubMed Central

    Rhee, Jiyoung; Kim, Gwi Eon; Lee, Chang Hyun; Kwon, Jung-Mi; Han, Sang-Hoon; Kim, Young Suk

    2014-01-01

    Tamoxifen and radiotherapy are used in breast cancer treatment worldwide. Radiation recall dermatitis (RRD), induced by tamoxifen, has been rarely reported. Herein, we report a RRD case induced by tamoxifen. A 47-year-old woman had a right quadrantectomy and an axillary lymph node dissection due to breast cancer. The tumor was staged pT2N0; it was hormone receptor positive, and human epidermal growth factor receptor 2 negative. The patient received adjuvant chemotherapy followed by tamoxifen and radiotherapy. After 22 months of tamoxifen, the patient developed a localized heating sensation, tenderness, edema, and redness at the irradiated area of the right breast. The symptoms improved within 1 week without treatment. Three weeks later, however, the patient developed similar symptoms in the same area of the breast. She continued tamoxifen before and during dermatitis, and symptoms resolved within 1 week. PMID:25568855

  15. Baicalin Inhibits IL-17-Mediated Joint Inflammation in Murine Adjuvant-Induced Arthritis

    PubMed Central

    Yang, Xue; Yang, Ji; Zou, Hejian

    2013-01-01

    T-helper-17 (Th17) cells are implicated in a number of inflammatory disorders including rheumatoid arthritis. Antagonism of Th17 cells is a treatment option for arthritis. Here, we report that Baicalin, a compound isolated from the Chinese herb Huangqin (Scutellaria baicalensis Georgi), relieved ankle swelling and protected the joint against inflammatory destruction in a murine adjuvant-induced arthritis model. Baicalin inhibited splenic Th17 cell population expansion in vivo. Baicalin prevented interleukin- (IL-) 17-mediated lymphocyte adhesion to cultured synoviocytes. Baicalin also blocked IL-17-induced intercellular adhesion molecule 1, vascular cell adhesion molecule 1, IL-6, and tumor necrosis factor-alpha mRNA expression in cultured synoviocytes. Collectively, these findings suggest that Baicalin downregulates the joint inflammation caused by IL-17, which is likely produced by an expanded population of splenic Th17 cells in experimental arthritis. Baicalin might be a promising novel therapeutic agent for treating rheumatoid arthritis in humans. PMID:23840239

  16. Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) evolution after silicone implants. Who is at risk?

    PubMed

    Goren, Idan; Segal, Gad; Shoenfeld, Yehuda

    2015-10-01

    Silicone implants have been in use since the mid-twentieth century, especially in the field of reconstructive breast surgery, and have long been considered as biologically inert and harmless. However, growing body of evidence from the past two decades links silicone with subsequent autoimmunity-related complications, collectively known as autoimmune/inflammatory syndrome induced by adjuvant--ASIA. Previous data suggest that while some patients tend to develop post-exposure autoimmune phenomena such as ASIA, other do not. However, thus far, no criteria for risk stratification were suggested. This current review summarizes the data linking silicone implants and autoimmunity, suggesting means of defining individuals who are at increased risk to develop silicone-induced ASIA, and therefore, a recommendation was made to avoid silicone implantation, e.g., individuals with previously diagnosed autoimmune disorders or with genetic preponderance for hyperactive immune system should not be considered as candidates for silicone implantation.

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

    PubMed Central

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

    2016-01-01

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

  18. Liposomes Containing Monophosphoryl Lipid A: A Potent Adjuvant System For Inducing Antibodies To Heroin Hapten Analogs

    PubMed Central

    Matyas, Gary R.; Mayorov, Alexander V.; Rice, Kenner C.; Jacobson, Arthur E.; Cheng, Kejun; Iyer, Malliga R.; Li, Fuying; Beck, Zoltan; Janda, Kim D.; Alving, Carl R.

    2014-01-01

    In order to create an effective immunization approach for a potential vaccine to heroin, liposomes containing monophosphoryl lipid A [L(MPLA)] were tested as an adjuvant system to induce antibodies to heroin hapten analogs. Four synthetic haptens and two immunization strategies were employed. In the first strategy, a hydrophobic 23 amino acid immunogenic peptide derived from the membrane proximal external region of gp41 from HIV-1 envelope protein was embedded as a carrier in the outer surface of L(MPLA), to which was conjugated a 15 amino acid universal T cell epitope and a terminal heroin hapten analog. In the second strategy, tetanus toxoid (TT) carrier protein was decorated with haptens by conjugation, and the hapten-conjugated protein was mixed with L(MPLA). After immunization of mice, each of the immunization strategies was effective for induction of IgG anti-hapten antibodies. The first immunization strategy induced a mean end-point IgG titer against one of two haptens tested of approximately 12,800; however, no detectable antibodies were induced against the liposome-associated HIV-1 carrier peptide. In the second immunization strategy, depending on the hapten used for decorating the TT, end-point IgG titers ranged from 100,000 to 6,500,000. In this strategy, in which hapten was conjugated to the TT, end-point IgG titers of 400,000 to the TT carrier were observed with each conjugate. However, upon mixing unconjugated TT with L(MPLA), anti-TT titers of 6,500,000 were observed. We conclude that L(MPLA) serves as a potent adjuvant for inducing antibodies to candidate heroin haptens. However, antibodies to the carrier peptide or protein were partly or completed inhibited by the presence of conjugated hapten. PMID:23624097

  19. Liposomes containing monophosphoryl lipid A: a potent adjuvant system for inducing antibodies to heroin hapten analogs.

    PubMed

    Matyas, Gary R; Mayorov, Alexander V; Rice, Kenner C; Jacobson, Arthur E; Cheng, Kejun; Iyer, Malliga R; Li, Fuying; Beck, Zoltan; Janda, Kim D; Alving, Carl R

    2013-06-10

    In order to create an effective immunization approach for a potential vaccine to heroin, liposomes containing monophosphoryl lipid A [L(MPLA)] were tested as an adjuvant system to induce antibodies to heroin hapten analogs. Four synthetic haptens and two immunization strategies were employed. In the first strategy, a hydrophobic 23 amino acid immunogenic peptide derived from the membrane proximal external region of gp41 from HIV-1 envelope protein was embedded as a carrier in the outer surface of L(MPLA), to which was conjugated a 15 amino acid universal T cell epitope and a terminal heroin hapten analog. In the second strategy, tetanus toxoid (TT) carrier protein was decorated with haptens by conjugation, and the hapten-conjugated protein was mixed with L(MPLA). After immunization of mice, each of the immunization strategies was effective for induction of IgG anti-hapten antibodies. The first immunization strategy induced a mean end-point IgG titer against one of two haptens tested of approximately 12,800; however, no detectable antibodies were induced against the liposome-associated HIV-1 carrier peptide. In the second immunization strategy, depending on the hapten used for decorating the TT, end-point IgG titers ranged from 100,000 to 6,500,000. In this strategy, in which hapten was conjugated to the TT, end-point IgG titers of 400,000 to the TT carrier were observed with each conjugate. However, upon mixing unconjugated TT with L(MPLA), anti-TT titers of 6,500,000 were observed. We conclude that L(MPLA) serves as a potent adjuvant for inducing antibodies to candidate heroin haptens. However, antibodies to the carrier peptide or protein were partly or completed inhibited by the presence of conjugated hapten. Published by Elsevier Ltd.

  20. Resin Monomers Act as Adjuvants in Ni-induced Allergic Dermatitis in vivo

    PubMed Central

    Bando, K.; Takahashi, H.; Kinbara, M.; Tanaka, Y.; Kuroishi, T.; Sasaki, K.; Takano-Yamamoto, T.; Sugawara, S.; Endo, Y.

    2014-01-01

    Resin monomers (RMs) are inflammatory agents and are thought to cause allergic contact dermatitis (ACD). However, mouse models are lacking, possibly because of the weak antigenicities of RMs. We previously reported that inflammatory substances can promote the allergic dermatitis (AD) induced by intradermally injected nickel (Ni-AD) in mice. Here, we examined the effects of RMs on Ni-AD. To sensitize mice to Ni, a mixture containing non-toxic concentrations of NiCl2 and an RM [either methyl methacrylate (MMA) or 2-hydroxyethyl methacrylate (HEMA)] was injected intraperitoneally or into ear-pinnae intradermally. Ten days later, a mixture containing various concentrations of NiCl2 and/or an RM was intradermally injected into ear-pinnae, and ear-swelling was measured. In adoptive transfer experiments, spleen cells from sensitized mice were transferred intravenously into non-sensitized recipients, and 24 h later NiCl2 was challenged to ear-pinnae. Whether injected intraperitoneally or intradermally, RM plus NiCl2 mixtures were effective in sensitizing mice to Ni. AD-inducing Ni concentrations were greatly reduced in the presence of MMA or HEMA (at the sensitization step from 10 mM to 5 or 50 µM, respectively, and at the elicitation step from 10 µM to 10 or 100 nM, respectively). These effects of RMs were weaker in IL-1-knockout mice and in macrophage-depleted mice. Cell-transfer experiments in IL-1-knockout mice indicated that both the sensitization and elicitation steps depended on IL-1. Challenge with an RM alone did not induce allergic ear-swelling in mice given the same RM + NiCl2 10 days before the challenge. These results suggest that RMs act as adjuvants, not as antigens, to promote Ni-AD by reducing the AD-inducing concentration of Ni, and that IL-1 and macrophages are critically important for the adjuvant effects. We speculate that what were previously thought of as “RM-ACD” might include ACD caused by antigens other than RMs that have undergone promotion

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

    NASA Astrophysics Data System (ADS)

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

    1989-12-01

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

  2. Gulf War syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA).

    PubMed

    Israeli, E

    2012-02-01

    Gulf War syndrome (GWS) is a multi-symptom condition comprising a variety of signs and symptoms described in the literature, which not been fully resolved. The various symptoms of the condition include muscle fatigue and tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep disturbances. In addition, excessive chemical sensitivity and odour intolerance is reported. The aetiology of the condition is unclear, but many reviews and epidemiological analyses suggest association with pyridostigmine bromide (PB), certain vaccination regimes, a variety of possible chemical exposures, including smoke from oil-well fires or depleted uranium from shells, as well as physical and psychological stress. Recently, Shoenfeld et al. suggested that four conditions--siliconosis, macrophagic myofaciitis (MMF), GWS and post-vaccination phenomena--that share clinical and pathogenic resemblances, may be incorporated into common syndrome called 'Autoimmune (Autoinflammatory) Syndrome induced by Adjuvants' (ASIA). Symptoms and signs of the four conditions described by Shoenfeld et al. show that at least eight out of ten main symptoms are in correlation in all four conditions. Namely, myalgia, arthralgias, chronic fatigue, neurological cognitive impairment, gastrointestinal symptoms, respiratory symptoms, skin manifestations and appearance of autoantibodies. Regardless of the aetiology of GWS, be it exposure to environmental factors or chemical drugs, vaccinations or the adjuvants in them, GWS fits well with the definition of ASIA and is included as part of 'Shoenfeld's syndrome'.

  3. Recombinant BCG Expressing LTAK63 Adjuvant induces Superior Protection against Mycobacterium tuberculosis.

    PubMed

    Nascimento, Ivan P; Rodriguez, Dunia; Santos, Carina C; Amaral, Eduardo P; Rofatto, Henrique K; Junqueira-Kipnis, Ana P; Gonçalves, Eduardo D C; D'Império-Lima, Maria R; Hirata, Mario H; Silva, Celio L; Winter, Nathalie; Gicquel, Brigitte; Mills, Kingston H G; Pizza, Mariagrazia; Rappuoli, Rino; Leite, Luciana C C

    2017-05-18

    In order to develop an improved BCG vaccine against tuberculosis we have taken advantage of the adjuvant properties of a non-toxic derivative of Escherichia coli heat labile enterotoxin (LT), LTAK63. We have constructed rBCG strains expressing LTAK63 at different expression levels. Mice immunized with BCG expressing low levels of LTAK63 (rBCG-LTAK63lo) showed higher Th1 cytokines and IL-17 in the lungs, and when challenged intratracheally with Mycobacterium tuberculosis displayed a 2.0-3.0 log reduction in CFU as compared to wild type BCG. Histopathological analysis of lung tissues from protected mice revealed a reduced inflammatory response. Immunization with rBCG-LTAK63lo also protected against a 100-fold higher challenge dose. Mice immunized with rBCG-LTAK63lo produced an increase in TGF-β as compared with BCG after challenge, with a corresponding reduction in Th1 and Th17 cytokines, as determined by Real Time RT-PCR. Furthermore, rBCG-LTAK63lo also displays protection against challenge with a highly virulent Beijing isolate. Our findings suggest that BCG with low-level expression of the LTAK63 adjuvant induces a stronger immune response in the lungs conferring higher levels of protection, and a novel mechanism subsequently triggers a regulatory immune response, which then limits the pathology. The rBCG-LTAK63lo strain can be the basis of an improved vaccine against tuberculosis.

  4. Evaluation of the immunoprophylactic potential of a killed vaccine candidate in combination with different adjuvants against murine visceral leishmaniasis.

    PubMed

    Thakur, Ankita; Kaur, Harpreet; Kaur, Sukhbir

    2015-02-01

    Despite a large number of field trials, till date no prophylactic antileishmanial vaccine exists for human use. Killed antigen formulations offer the advantage of being safe but they have limited immunogenicity. Recent research has documented that efforts to develop effective Leishmania vaccine have been limited due to the lack of an appropriate adjuvant. Addition of adjuvants to vaccines boosts and directs the immunogenicity of antigens. So, the present study was done to evaluate the effectiveness of four adjuvants i.e. alum, saponin, cationic liposomes and monophosphoryl lipid-A in combination with Autoclaved Leishmania donovani (ALD) antigen against murine visceral leishmaniasis (VL). BALB/c mice were immunized thrice with respective vaccine formulation. Two weeks after last booster, challenge infection was given. Mice were sacrificed 15 days after last immunization and on 30, 60 and 90 post infection/challenge days. A considerable protective efficacy was shown by all vaccine formulations. It was evident from significant reduction in parasite load, profound delayed type hypersensitivity responses (DTH), increased IgG2a titres and high levels of Th1 cytokines (IFN-γ, IL-12) as compared to the infected controls. However, level of protection varied with the type of adjuvant used. Maximum protection was achieved with the use of liposome encapsulated ALD antigen and it was closely followed by group immunized with ALD+MPL-A. Significant results were also obtained with ALD+saponin, ALD+alum and ALD antigen (alone) but the protective efficacy was reduced as compared to other immunized groups. The present study reveals greater efficacy of two vaccine formulations i.e. ALD+liposome and ALD+MPL-A against murine VL.

  5. Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus

    PubMed Central

    Bagnoli, Fabio; Fontana, Maria Rita; Soldaini, Elisabetta; Mishra, Ravi P. N.; Fiaschi, Luigi; Cartocci, Elena; Nardi-Dei, Vincenzo; Ruggiero, Paolo; Nosari, Sarah; De Falco, Maria Grazia; Lofano, Giuseppe; Marchi, Sara; Galletti, Bruno; Mariotti, Paolo; Bacconi, Marta; Torre, Antonina; Maccari, Silvia; Scarselli, Maria; Rinaudo, C. Daniela; Inoshima, Naoko; Savino, Silvana; Mori, Elena; Rossi-Paccani, Silvia; Baudner, Barbara; Pallaoro, Michele; Swennen, Erwin; Petracca, Roberto; Brettoni, Cecilia; Liberatori, Sabrina; Norais, Nathalie; Monaci, Elisabetta; Bubeck Wardenburg, Juliane; Schneewind, Olaf; O’Hagan, Derek T.; Valiante, Nicholas M.; Bensi, Giuliano; Bertholet, Sylvie; De Gregorio, Ennio; Rappuoli, Rino; Grandi, Guido

    2015-01-01

    Both active and passive immunization strategies against Staphylococcus aureus have thus far failed to show efficacy in humans. With the attempt to develop an effective S. aureus vaccine, we selected five conserved antigens known to have different roles in S. aureus pathogenesis. They include the secreted factors α-hemolysin (Hla), ess extracellular A (EsxA), and ess extracellular B (EsxB) and the two surface proteins ferric hydroxamate uptake D2 and conserved staphylococcal antigen 1A. The combined vaccine antigens formulated with aluminum hydroxide induced antibodies with opsonophagocytic and functional activities and provided consistent protection in four mouse models when challenged with a panel of epidemiologically relevant S. aureus strains. The importance of antibodies in protection was demonstrated by passive transfer experiments. Furthermore, when formulated with a toll-like receptor 7-dependent (TLR7) agonist recently designed and developed in our laboratories (SMIP.7–10) adsorbed to alum, the five antigens provided close to 100% protection against four different staphylococcal strains. The new formulation induced not only high antibody titers but also a Th1 skewed immune response as judged by antibody isotype and cytokine profiles. In addition, low frequencies of IL-17–secreting T cells were also observed. Altogether, our data demonstrate that the rational selection of mixtures of conserved antigens combined with Th1/Th17 adjuvants can lead to promising vaccine formulations against S. aureus. PMID:25775551

  6. Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques.

    PubMed

    Sui, Yongjun; Zhu, Qing; Gagnon, Susan; Dzutsev, Amiran; Terabe, Masaki; Vaccari, Monica; Venzon, David; Klinman, Dennis; Strober, Warren; Kelsall, Brian; Franchini, Genoveffa; Belyakov, Igor M; Berzofsky, Jay A

    2010-05-25

    Adjuvant effects on innate as well as adaptive immunity may be critical for inducing protection against mucosal HIV and simian immunodeficiency virus (SIV) exposure. We therefore studied effects of Toll-like receptor agonists and IL-15 as mucosal adjuvants on both innate and adaptive immunity in a peptide/poxvirus HIV/SIV mucosal vaccine in macaques, and made three critical observations regarding both innate and adaptive correlates of protection: (i) adjuvant-alone without vaccine antigen impacted the intrarectal SIVmac251 challenge outcome, correlating with surprisingly long-lived APOBEC3G (A3G)-mediated innate immunity; in addition, even among animals receiving vaccine with adjuvants, viral load correlated inversely with A3G levels; (ii) a surprising threshold-like effect existed for vaccine-induced adaptive immunity control of viral load, and only antigen-specific polyfunctional CD8(+) T cells correlated with protection, not tetramer(+) T cells, demonstrating the importance of T-cell quality; (iii) synergy was observed between Toll-like receptor agonists and IL-15 for driving adaptive responses through the up-regulation of IL-15Ralpha, which can present IL-15 in trans, as well as for driving the innate A3G response. Thus, strategic use of molecular adjuvants can provide better mucosal protection through induction of both innate and adaptive immunity.

  7. Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

    PubMed Central

    Sui, Yongjun; Zhu, Qing; Gagnon, Susan; Dzutsev, Amiran; Terabe, Masaki; Vaccari, Monica; Venzon, David; Klinman, Dennis; Strober, Warren; Kelsall, Brian; Franchini, Genoveffa; Belyakov, Igor M.; Berzofsky, Jay A.

    2010-01-01

    Adjuvant effects on innate as well as adaptive immunity may be critical for inducing protection against mucosal HIV and simian immunodeficiency virus (SIV) exposure. We therefore studied effects of Toll-like receptor agonists and IL-15 as mucosal adjuvants on both innate and adaptive immunity in a peptide/poxvirus HIV/SIV mucosal vaccine in macaques, and made three critical observations regarding both innate and adaptive correlates of protection: (i) adjuvant-alone without vaccine antigen impacted the intrarectal SIVmac251 challenge outcome, correlating with surprisingly long-lived APOBEC3G (A3G)-mediated innate immunity; in addition, even among animals receiving vaccine with adjuvants, viral load correlated inversely with A3G levels; (ii) a surprising threshold-like effect existed for vaccine-induced adaptive immunity control of viral load, and only antigen-specific polyfunctional CD8+ T cells correlated with protection, not tetramer+ T cells, demonstrating the importance of T-cell quality; (iii) synergy was observed between Toll-like receptor agonists and IL-15 for driving adaptive responses through the up-regulation of IL-15Rα, which can present IL-15 in trans, as well as for driving the innate A3G response. Thus, strategic use of molecular adjuvants can provide better mucosal protection through induction of both innate and adaptive immunity. PMID:20457926

  8. Complete Remission of Unresectable Hepatocellular Carcinoma After Combined Sorafenib and Adjuvant Yttrium-90 Radioembolization.

    PubMed

    Lorenzin, Dario; Pravisani, Riccardo; Leo, Cosimo Alex; Bugiantella, Walter; Soardo, Giorgio; Carnelutti, Alessia; Umberto, Baccarani; Risaliti, Andrea

    2016-03-01

    Sorafenib has improved the median overall survival of unresectable or otherwise untreatable hepatocellular carcinoma (HCC) of ∼3 months, compared to supportive cares. Complete response, although rare, has been reported. The authors reported herein a case of complete biochemical and radiological remission of advanced unresectable HCC with lymph node metastasis and tumoral portal vein thrombosis treated by 5 months therapy with sorafenib followed by adjuvant Yttrium-90 radioembolization. At 12 months follow-up, there is no evidence of HCC recurrence.

  9. A novel non-toxic combined CTA1-DD and ISCOMS adjuvant vector for effective mucosal immunization against influenza virus.

    PubMed

    Eliasson, Dubravka Grdic; Helgeby, Anja; Schön, Karin; Nygren, Caroline; El-Bakkouri, Karim; Fiers, Walter; Saelens, Xavier; Lövgren, Karin Bengtsson; Nyström, Ida; Lycke, Nils Y

    2011-05-23

    Here we demonstrate that by using non-toxic fractions of saponin combined with CTA1-DD we can achieve a safe and above all highly efficacious mucosal adjuvant vector. We optimized the construction, tested the requirements for function and evaluated proof-of-concept in an influenza A virus challenge model. We demonstrated that the CTA1-3M2e-DD/ISCOMS vector provided 100% protection against mortality and greatly reduced morbidity in the mouse model. The immunogenicity of the vector was superior to other vaccine formulations using the ISCOM or CTA1-DD adjuvants alone. The versatility of the vector was best exemplified by the many options to insert, incorporate or admix vaccine antigens with the vector. Furthermore, the CTA1-3M2e-DD/ISCOMS could be kept 1 year at 4°C or as a freeze-dried powder without affecting immunogenicity or adjuvanticity of the vector. Strong serum IgG and mucosal IgA responses were elicited and CD4 T cell responses were greatly enhanced after intranasal administration of the combined vector. Together these findings hold promise for the combined vector as a mucosal vaccine against influenza virus infections including pandemic influenza. The CTA1-DD/ISCOMS technology represents a breakthrough in mucosal vaccine vector design which successfully combines immunomodulation and targeting in a safe and stable particulate formation.

  10. A multi-subunit chlamydial vaccine induces antibody and cell-mediated immunity in immunized koalas (Phascolarctos cinereus): comparison of three different adjuvants.

    PubMed

    Carey, Alison J; Timms, Peter; Rawlinson, Galit; Brumm, Jacqui; Nilsson, Karen; Harris, Jonathon M; Beagley, Kenneth W

    2010-02-01

    Chlamydial infections represent a major threat to the survival of the koala. Infections caused by Chlamydia pecorum cause blindness, infertility, pneumonia and urinary tract infections and represent a threat to the survival of the species. Little is known about the immune response in koalas, or the safety of commonly used adjuvants for induction of protective systemic and mucosal immunity. of study In the present study, we immunized 18 healthy female koalas subcutaneously with a combination of three chlamydial antigens [major outer membrane protein (MOMP), NrdB and TC0512 (Omp85)] mixed with one of three different adjuvants [Alhydrogel, Immunostimulating Complex (ISC) and TiterMax Gold]. All adjuvants induced strong neutralizing IgG responses in plasma against the three antigens with prolonged responses lasting more than 270 days seen in Alhydrogel and ISC immunized animals. Cloacal IgG responses lasting >270 days were also induced in ISC-immunized animals. Chlamydia-specific peripheral blood mononuclear cell proliferative responses were elicited by both Alhydrogel and ISC, and these lasted >270 days in the ISC group. The data show that a multi-subunit chlamydial vaccine, given subcutaneously, can elicit Chlamydia-specific cell-mediated and antibody responses in the koala demonstrating that the development of a protective vaccine is feasible.

  11. Astragali radix: could it be an adjuvant for oxaliplatin-induced neuropathy?

    PubMed

    Di Cesare Mannelli, Lorenzo; Pacini, Alessandra; Micheli, Laura; Femia, Angelo Pietro; Maresca, Mario; Zanardelli, Matteo; Vannacci, Alfredo; Gallo, Eugenia; Bilia, Anna Rita; Caderni, Giovanna; Firenzuoli, Fabio; Mugelli, Alessandro; Ghelardini, Carla

    2017-02-10

    Neurotoxicity is a major side effect of platinum derivatives both during and after treatment. In the absence of effective pharmacological compounds, the opportunity to identify safe adjuvant treatments among medicinal plants seems appropriate. Astragali radix is an adaptogenic herbal product recently analyzed in platinum-treated cancer patients. With the aim of evaluating the anti-neuropathic profile of Astragali radix, a previously characterized aqueous (Aqu) and two hydroalcoholic (20%HA and 50%HA) extracts were tested in a rat model of oxaliplatin-induced neuropathy. Repeated administrations significantly reduced oxaliplatin-dependent hypersensitivity with 50%HA, the most effective, fully preventing mechanical and thermal hypersensitivity. Ex vivo, 50%HA reduced morphometric and molecular alterations induced by oxaliplatin in peripheral nerve and dorsal-root-ganglia. In the spinal cord and in brain areas, 50%HA significantly decreased activation of microglia and astrocytes. Furthermore, 50%HA prevented the nephro- and hepato-toxicity induced by the anticancer drug. The protective effect of 50%HA did not alter oxaliplatin-induced apoptosis in colon tumors of Pirc rats, an Apc-driven model of colon carcinogenesis. The hydroalcoholic extract (50%HA) of Astragali radix relieves pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced neuropathy.

  12. Astragali radix: could it be an adjuvant for oxaliplatin-induced neuropathy?

    PubMed Central

    Di Cesare Mannelli, Lorenzo; Pacini, Alessandra; Micheli, Laura; Femia, Angelo Pietro; Maresca, Mario; Zanardelli, Matteo; Vannacci, Alfredo; Gallo, Eugenia; Bilia, Anna Rita; Caderni, Giovanna; Firenzuoli, Fabio; Mugelli, Alessandro; Ghelardini, Carla

    2017-01-01

    Neurotoxicity is a major side effect of platinum derivatives both during and after treatment. In the absence of effective pharmacological compounds, the opportunity to identify safe adjuvant treatments among medicinal plants seems appropriate. Astragali radix is an adaptogenic herbal product recently analyzed in platinum-treated cancer patients. With the aim of evaluating the anti-neuropathic profile of Astragali radix, a previously characterized aqueous (Aqu) and two hydroalcoholic (20%HA and 50%HA) extracts were tested in a rat model of oxaliplatin-induced neuropathy. Repeated administrations significantly reduced oxaliplatin-dependent hypersensitivity with 50%HA, the most effective, fully preventing mechanical and thermal hypersensitivity. Ex vivo, 50%HA reduced morphometric and molecular alterations induced by oxaliplatin in peripheral nerve and dorsal-root-ganglia. In the spinal cord and in brain areas, 50%HA significantly decreased activation of microglia and astrocytes. Furthermore, 50%HA prevented the nephro- and hepato-toxicity induced by the anticancer drug. The protective effect of 50%HA did not alter oxaliplatin-induced apoptosis in colon tumors of Pirc rats, an Apc-driven model of colon carcinogenesis. The hydroalcoholic extract (50%HA) of Astragali radix relieves pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced neuropathy. PMID:28186109

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

    PubMed Central

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

    2015-01-01

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

  14. Therapeutic effect of melittin on a rat model of chronic prostatitis induced by Complete Freund's Adjuvant.

    PubMed

    Lin, Li; Zhu, Bao-Ping; Cai, Liang

    2017-06-01

    The present study was aimed to establish a model of chronic prostatitis in rat with the use of intraprostatic injection of Complete Freund's Adjuvant, and to examine the anti-inflammatory and analgesic effects of melittin on the newly-developed chronic prostatic pain model. Adult male Sprague-Dawley rats were injected with Complete Freund's Adjuvant (CFA) into the prostate. Twelve days after model rats of the treatment group were injected melittin into the prostate, while those of the control group received sterile saline injection. The nociceptive effects of CFA were evaluated by using a behavior approach (i.e. mechanical pain threshold measurement) on the day of CFA injection and 6, 12, and 18days after CFA injection. After the in-live study was done, the prostate was collected for histological examination of inflammatory cell infiltration. Levels of cyclooxygenase (COX)-2 in prostate and glial fibrillary acidic protein (GFAP) in spinal cord were determined using immunohistochemistry. Rats of the sham control group received intraprostatic injection of sterile saline and were studied using the same methods RESULTS: Intraprostatic CFA injection induced local allodynia that lasted over at least 2 weeks. The pain behavior of rat was associated with increases in inflammatory cell infiltration into the prostate. Levels of COX-2 in prostate and GFAP in spinal cord were also elevated. Treatment with melittin significantly raised pain threshold, decreased inflammatory infiltrates, and suppressed COX-2 and GFAP expression. Intraprostatic injection of CFA induced neurogenic prostatitis and prostatic pain. The established model will be useful to the study of CP/CPPS pathogenesis. Melittin demonstrated profound anti-inflammatory and analgesic effects on the chronic prostatic pain model, suggesting melittin may hold promise as a novel therapeutic for treatment of CP/CPPS. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

    PubMed

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

    2012-08-01

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

  16. Investigation of the effect of phlomisoside F on complete Freund's adjuvant-induced arthritis

    PubMed Central

    Zhang, Xiuying; Dong, Yanfeng; Dong, Hanyu; Zhang, Wen; Li, Fang

    2017-01-01

    Phlomis younghusbandii Mukerjee (Labiatae) has been reported to be effective in the treatment of rheumatoid arthritis (RA). In the present study, the anti-inflammatory and anti-arthritic effects of phlomisoside F (PF), isolated from P. younghusbandii Mukerjee (Labiatae), were investigated in male Wistar rats subjected to carrageen-induced paw edema and complete Freund's adjuvant (CFA)-induced arthritis. Arthritis scores were evaluated by a 5-point ordinal scale (scores 0–4). Expression levels of TNF-α, IL-1β, IL-6, IL-10, COX-2 and 5-LOX were determined via ELISA and western blot assays. Subsequent to establishing the edema and arthritis models, oral administration of PF (5, 10 and 20 mg/kg) significantly inhibited mean edema rate, compared with the control group in carrageenan-induced paw edema assay. In addition, administration of PF (5, 10 and 20 mg/kg/day) for 28 days markedly exhibited an anti-arthritic activity by offsetting the body weight loss, inhibiting the paw edema, reducing the arthritis scores and the indices of thymus and spleen, inhibiting the expression levels of TNF-α, IL-1β, IL-6, COX-2 and 5-LOX, and increasing the expression of IL-10, when compared with the respective control group in CFA-induced arthritis assay. In conclusion, PF is a valuable anti-arthritic constituent of P. younghusbandii, and the present study results suggest that this herb may be used in the treatment of RA. PMID:28352356

  17. CCL17 combined with CCL19 as a nasal adjuvant enhances the immunogenicity of an anti-caries DNA vaccine in rodents

    PubMed Central

    Yan, Yan-hong; Yu, Fei; Zeng, Chang; Cao, Li-hua; Zhang, Zhou; Xu, Qing-an

    2016-01-01

    Aim: CCL19 and its receptor CCR7 are essential molecules for facilitating the trafficking of mature dendritic cells (DCs) and helping to establish a microenvironment in lymphoid tissues to initiate primary immune responses, whereas CCL17 is required in the CCR7-CCL19-dependent migration of DCs. In this study we examined whether co-administration of CCL17 and CCL19 could enhance the immunogenicity of an anti-caries DNA vaccine, pCIA-P, in rodents. Methods: Plasmids encoding CCL17 (pCCL17/VAX) and CCL19 (pCCL19/VAX) were constructed. BALB/c mice were intranasally administered pCCL17/VAX, pCCL19/VAX, or pCCL17/VAX plus pCCL19/VAX, the migration of DCs to the spleen and draining lymph nodes (DLNs) was assessed with flow cytometry. The mice were co-administered pCIA-P; and the anti-PAc antibodies in the serum and saliva were detected with ELISA. Wistar rats were orally challenged with Streptococcus mutans and then administered pCIA-P in combination with pCCL17/VAX, pCCL19/VAX, or pCCL17/VAX plus pCCL19/VAX. The amount of S mutans sustained on rat molar surfaces was assessed using a colony forming assay. Caries activity was scored with the Keyes method. Results: Co-administration of the CCL17 and CCL19 genes in mice caused a greater increase in the number of mature DCs in the spleen and DLNs compared with administration of CCL17 or CCL19 genes alone. CCL17 and CCL19 double-adjuvant plus pCIA-P induced significantly higher levels of anti-PAc salivary IgA and anti-PAc serum IgG antibody in mice, and strengthened the ability of pCIA-P in inhibiting the colonization of S mutans on rat tooth surfaces. The caries activity of the combined adjuvant group was significantly lower than that of the pCCL17/VAX or the pCCL19/VAX group. Conclusion: A nasal adjuvant consisting of a combination of CCL17 and CCL19 attracts more mature DCs to secondary lymphoid tissues, inducing enhanced antibody responses against the anti-caries DNA vaccine pCIA-P and reducing S mutans infection in

  18. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity.

    PubMed

    Didierlaurent, Arnaud M; Morel, Sandra; Lockman, Laurence; Giannini, Sandra L; Bisteau, Michel; Carlsen, Harald; Kielland, Anders; Vosters, Olivier; Vanderheyde, Nathalie; Schiavetti, Francesca; Larocque, Daniel; Van Mechelen, Marcelle; Garçon, Nathalie

    2009-11-15

    Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-kappaB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4(+) T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.

  19. Influence of formulation pH and suspension state on freezing-induced agglomeration of aluminum adjuvants.

    PubMed

    Salnikova, Maya S; Davis, Harrison; Mensch, Christopher; Celano, Lauren; Thiriot, David S

    2012-03-01

    Freezing and thawing of vaccines containing aluminum adjuvants can lead to formation of aggregates and loss in vaccine potency. We sought to understand whether and to what extent the freeze-thaw damage to aluminum adjuvants would differ based on suspension state (flocculation and settlement) at the time of freezing. As flocculation and settlement characteristics of aluminum adjuvants are driven largely by the electrostatic charges on the adjuvant particles, which, in turn, are strongly influenced by the pH of the suspension, we conducted freeze-thaw studies on both Adjuphos and Alhydrogel™ samples at three pH levels (4, 6.5, and 7.2) in buffer solutions with 9% sucrose. Significantly less aggregation occurred in the buffered sucrose solutions at the pH furthest from the aluminum adjuvant point of zero charge during slow freezing at -20°C. The freezing-induced aggregation for the samples with 9% sucrose at each pH was minimal during fast freezing at -70°C and -115°C. Suspensions that were flocculated and settled to a greater extent experienced the most freeze-thaw aggregation, whereas suspensions that were frozen before significant flocculation and settlement occurred showed little or no aggregation. Because pH of formulation can affect flocculation and settling time, it indirectly affects the extent of freeze-thaw aggregation. Copyright © 2011 Wiley Periodicals, Inc.

  20. [Influenza vaccine and adjuvant].

    PubMed

    Nakayama, Tetsuo

    2011-01-01

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

  1. In ovo vaccination using Eimeria profilin and Clostridium perfringens NetB proteins in Montanide IMS adjuvant increases protective immunity against experimentally-induced necrotic enteritis.

    PubMed

    Lillehoj, Hyun Soon; Jang, Seung Ik; Panebra, Alfredo; Lillehoj, Erik Peter; Dupuis, Laurent; Ben Arous, Juliette; Lee, Seung Kyoo; Oh, Sung Taek

    2017-10-01

    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. 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. 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. 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 NetB proteins, and may reduce disease pathology by

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

    PubMed

    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.

  3. Anti-arthritic activity of ethanol extract of Claoxylon indicum on Freund's complete adjuvant-induced arthritis in mice.

    PubMed

    Chen, Yong; Wang, Qi-Wen; Zuo, Jian; Chen, Jian-Wei; Li, Xiang

    2017-01-05

    Claoxylon indicum Hassk. (Euphorbiaceae), named Diu Le Bang, have functions of dehumidification and relieving swelling pain, and is used as a folk medicine to treat Rheumatoid arthritis (RA), lumbocrural pain and foot edema in the south of China. The aim of the present study was to investigate the anti-arthritic activity of the ethanol extract of Claoxylon indicum (CIE) on mice with adjuvant induced joint arthritis. Adjuvant arthritis was induced in mice by subcutaneous injection of complete Freund's adjuvant into the plantar surface of right hind paw. Arthritis severity was evaluated by arthritic score, hind paws oedema and spleen index, and histological examinations. Serum samples were collected for determination of malondialdehyde (MDA) and alkaline phosphatase (ALP) levels. The expression of interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) in the specimens of knee joints was determined by standard immunohistochemical techniques. CIE administration (0.4 and 0.8 g/kg) suppressed the inflammatory responses in the joints of adjuvant-induced arthritis (AIA) mice, suggested by the modulatory effects on paw swelling, hyperplasia of lymphatic tissues and synovial membrane. It also decreased the levels of MDA and ALP in serum and downregulated the expression of IL-1β and TNF-α in the arthritic joints of AIA mice. These results suggested that CIE possessed substantial anti-arthritic activity due to immumodepression and regulation of cytokines. CIE may be a potential candidate for the treatment of RA.

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

    SciTech Connect

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

    2009-09-18

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

  5. CCR5 small interfering RNA ameliorated joint inflammation in rats with adjuvant-induced arthritis.

    PubMed

    Duan, Hongmei; Yang, Pingting; Fang, Fang; Ding, Shuang; Xiao, Weiguo

    2014-12-01

    Rheumatoid arthritis (RA) is a systemic inflammatory disease. C-C chemokine receptor type 5 (CCR5) is found in inflamed synovium of RA patients and is necessary for formation of RA. We aimed to check whether delivery of CCR5-specific small interfering RNA (siRNA) via electroporation suppresses local inflammation in arthritis rats. Vectors encoding siRNA that target CCR5 or negative control siRNA were constructed for gene silencing and the silencing effects of suppressing CCR5 expression in synovium examined by western blot. The vector with strongest effect was delivered into the knee joint of adjuvant-induced arthritis (AIA) rats by the in vivo electroporation method 7, 10, 13, and 16 days after immunization with Complete Freund's adjuvant. During an observation of 28 days, behavior, paw swelling, arthritis and histopathologic scoring were estimated. The expression level of CCR5 in synovium was evaluated by western blot and real-time PCR. Anti-CCR5 D1 siRNA was effectively inhibited CCR5 expression in vitro. Moreover, delivery of the siRNA into inflammatory joint also suppressed the expression of CCR5 in vivo and markedly suppressed paw swelling and inflammation. Local electroporation of anti-CCR5 siRNA into the left inflamed joints could achieve the silencing of CCR5 gene and alleviate local inflammation just in the knee joint injected with siRNA other than the opposite joint. Inhibition of CCR5 expression may provide a potential for treatment of RA.

  6. The Endogenous Adjuvant Squalene Can Induce a Chronic T-Cell-Mediated Arthritis in Rats

    PubMed Central

    Carlson, Barbro C.; Jansson, Åsa M.; Larsson, Anders; Bucht, Anders; Lorentzen, Johnny C.

    2000-01-01

    Squalene is a cholesterol precursor, which stimulates the immune system nonspecifically. We demonstrate that one intradermal injection of this adjuvant lipid can induce joint-specific inflammation in arthritis-prone DA rats. Histopathological and immunohistochemical analyses revealed erosion of bone and cartilage, and that development of polyarthritis coincided with infiltration of αβ+ T cells. Depletion of these cells with anti-αβ TcR monoclonal antibody (R73) resulted in complete recovery, whereas anti-CD8 and anti-γδ TcR injections were ineffective. The apparent dependence on CD4+ T cells suggested a role for genes within the major histocompatibility complex (MHC), and this was concluded from comparative studies of MHC congenic rat strains, in which DA.1H rats were less susceptible than DA rats. Furthermore, LEW.1AV1 and PVG.1AV1 rats with MHC identical to DA rats were arthritis-resistant, demonstrating that non-MHC genes also determine susceptibility. Some of these genetic influences could be linked to previously described arthritis susceptibility loci in an F2 intercross between DA and LEW.1AV1 rats (ie, Cia3, Oia2 and Cia5). Interestingly, some F2 hybrid rats developed chronic arthritis, a phenotype not apparent in the parental inbred strains. Our demonstration that an autoadjuvant can trigger chronic, immune-mediated joint-specific inflammation may give clues to the pathogenesis of rheumatoid arthritis, and it raises new questions concerning the role of endogenous molecules with adjuvant properties in chronic inflammatory diseases. PMID:10854227

  7. Poly I:C adjuvanted inactivated swine influenza vaccine induces heterologous protective immunity in pigs.

    PubMed

    Thomas, Milton; Wang, Zhao; Sreenivasan, Chithra C; Hause, Ben M; Gourapura J Renukaradhya; Li, Feng; Francis, David H; Kaushik, Radhey S; Khatri, Mahesh

    2015-01-15

    Swine influenza is widely prevalent in swine herds in North America and Europe causing enormous economic losses and a public health threat. Pigs can be infected by both avian and mammalian influenza viruses and are sources of generation of reassortant influenza viruses capable of causing pandemics in humans. Current commercial vaccines provide satisfactory immunity against homologous viruses; however, protection against heterologous viruses is not adequate. In this study, we evaluated the protective efficacy of an intranasal Poly I:C adjuvanted UV inactivated bivalent swine influenza vaccine consisting of Swine/OH/24366/07 H1N1 and Swine/CO/99 H3N2, referred as PAV, in maternal antibody positive pigs against an antigenic variant and a heterologous swine influenza virus challenge. Groups of three-week-old commercial-grade pigs were immunized intranasally with PAV or a commercial vaccine (CV) twice at 2 weeks intervals. Three weeks after the second immunization, pigs were challenged with the antigenic variant Swine/MN/08 H1N1 (MN08) and the heterologous Swine/NC/10 H1N2 (NC10) influenza virus. Antibodies in serum and respiratory tract, lung lesions, virus shedding in nasal secretions and virus load in lungs were assessed. Intranasal administration of PAV induced challenge viruses specific-hemagglutination inhibition- and IgG antibodies in the serum and IgA and IgG antibodies in the respiratory tract. Importantly, intranasal administration of PAV provided protection against the antigenic variant MN08 and the heterologous NC10 swine influenza viruses as evidenced by significant reductions in lung virus load, gross lung lesions and significantly reduced shedding of challenge viruses in nasal secretions. These results indicate that Poly I:C or its homologues may be effective as vaccine adjuvants capable of generating cross-protective immunity against antigenic variants/heterologous swine influenza viruses in pigs.

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

    PubMed Central

    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

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

    PubMed Central

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

    2014-01-01

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

  10. Survival benefit associated with adjuvant androgen deprivation therapy combined with radiotherapy for high- and low-risk patients with nonmetastatic prostate cancer

    SciTech Connect

    Zeliadt, Steven B. . E-mail: szeliadt@fhcrc.org; Potosky, Arnold L.; Penson, David F.

    2006-10-01

    Background: The use of adjuvant androgen deprivation therapy (ADT) combined with radiotherapy has become common in low-risk patients, although clinical trials have focused primarily on high-risk patients. This study examines the effectiveness of adjuvant ADT combined with radiotherapy for a wide range of patients treated in the 1990s. Methods and Materials: Prostate cancer survival was examined in a population based cohort of 31,643 patients aged 65 to 85 years who were diagnosed with nonmetastatic prostate cancer and treated with external beam radiotherapy and/or brachytherapy. Instrumental variable analysis methods were used to control for selection bias. Results: Patients with stage T3/T4 disease who received adjuvant ADT experienced improved 5-year and 8-year survival. No survival advantage was observed for men with T1/T2 disease during this interval. Conclusion: High-risk patients who receive primary radiotherapy have benefited from adjuvant ADT, whereas low-risk patients with disease confined to the prostate have not yet benefited from adjuvant therapy within the first 8 years after treatment. These findings are consistent with practice guidelines, which recommend adjuvant ADT for patients with high-risk disease.

  11. Adjuvant quercetin therapy for combined treatment of epilepsy and comorbid depression.

    PubMed

    Singh, Tanveer; Kaur, Taranjot; Goel, Rajesh Kumar

    2017-03-01

    Epilepsy is one of the major neurological disorders frequently associated with psychiatric disorders such as depression. The predisposition of tryptophan metabolism towards kynurenine pathway has been reported as one of the plausible reasons for association of depression in epilepsy. Hence, this study was envisaged to evaluate the dose dependent inhibition of indoleamine 2,3-dioxygenase (IDO) enzyme employing quercetin (screened employing in vitro method) with levetiracetam for combined management of epilepsy and comorbid depression. Kindling was induced in male swiss albino mice by administration of pentylenetetrazole subconvulsive doses (35 mg/kg, i.p.) at an interval of 48 ± 2 h. Kindled animals were treated with vehicle, levetiracetam (40 mg/kg/day i.p.) levetiracetam in combination with different doses of quercetin (10 mg/kg; 20 mg/kg; 40 mg/kg)/day/p.o. for 15 days. Except naïve, all the groups were challenged with pentylenetetrazole (35 mg/kg i.p.) on day 5, 10, and 15 to evaluate the seizure severity score. Depression was evaluated in all experimental groups using the tail suspension and sucrose preference test on days 1, 5, 10 and 15, 2 h after pentylenetetrazole challenge. Results suggested that vehicle treated kindled animals were significantly associated with depression. Chronic levetiracetam treatment significantly reduced seizure severity score, but further worsened the associated depression. Quercetin supplementation with levetiracetam dose dependently ameliorated depression associated with epilepsy. Neurochemical and biochemical findings also supported the behavioural findings of the study. Thus, our results suggested that supplementation of quercetin with levetiracetam could be explored further for combined treatment of epilepsy and comorbid depression.

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

    PubMed

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

    2015-08-01

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

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

    PubMed Central

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

    2015-01-01

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

  14. Protective effect of latex of Calotropis procera in Freund's Complete Adjuvant induced monoarthritis.

    PubMed

    Kumar, V L; Roy, S

    2009-01-01

    The protective effect of latex of Calotropis procera in Freund's Complete Adjuvant (FCA) induced monoarticular arthritis was evaluated in rats. Arthritis was induced by a single intra-articular injection of 0.1 mL of 0.1% FCA in the right ankle joint. The effect of dried latex (DL, 200 and 400 mg/kg) and its methanol extract (MeDL, 50 and 500 mg/kg) following oral administration was evaluated on joint inflammation, hyperalgesia, locomotor function and histology at the time of peak inflammation. The effects of DL and MeDL were compared with antiinflammatory drugs phenylbutazone (100 mg/kg), prednisolone (20 mg/kg), rofecoxib (20 and 100 mg/kg) and immuno-suppressant methotrexate (0.3 mg/kg). Daily oral administration of DL and its methanol extract (MeDL) produced a significant reduction in joint inflammation (about 50% and 80% inhibition) and associated hyperalgesia. The antihyperalgesic effect of MeDL was comparable to that of rofecoxib. Both DL and MeDL produced a marked improvement in the motility and stair climbing ability of the rats. The histological analysis of the arthritic joint also revealed significant reduction in oedema and cellular infiltration by MeDL that was comparable to that of rofecoxib. Thus, our study suggests that the latex of C. procera has the potential to be used as an antiarthritic agent. Copyright 2008 John Wiley & Sons, Ltd.

  15. Morphological changes in hind limb muscles elicited by adjuvant-induced arthritis of the rat knee.

    PubMed

    Ozawa, J; Kurose, T; Kawamata, S; Yamaoka, K

    2010-02-01

    We investigated qualitative and quantitative changes in rat hind limb muscles caused by complete Freund's adjuvant (CFA)-induced knee joint pain. One week after CFA injection, muscle atrophy was induced only on the CFA-injected side. Wet weight of the rectus femoris (RF) and soleus (SOL) muscles were significantly decreased by 20% and 19%, respectively. The reduction in cross-sectional areas by CFA was similar for fast and slow muscle fibers in the RF (10% vs 15%, respectively) and SOL muscles (16% vs 16%, respectively). At the light microscopic level, pathological changes were not found in the RF muscles on both sides, although the infiltration of mononuclear cells and muscle regeneration were found in the SOL muscles on CFA-injected and contralateral control sides. On the other hand, electron microscopy revealed degenerative changes in the RF and SOL muscles on the CFA-injected side. Interestingly, sarcomere hypercontraction, indicating overexercise, was observed to a limited extent in the SOL muscles on the control side. In conclusions, knee joint pain can trigger the rapid development of muscle atrophy with degenerative changes not only in thigh but also calf muscles. This indicates that early interventions to inhibit joint pain or inflammation may prevent muscle atrophy.

  16. Copper chelation with tetrathiomolybdate suppresses adjuvant-induced arthritis and inflammation-associated cachexia in rats

    PubMed Central

    Omoto, Atsushi; Kawahito, Yutaka; Prudovsky, Igor; Tubouchi, Yasunori; Kimura, Mizuho; Ishino, Hidetaka; Wada, Makoto; Yoshida, Makie; Kohno, Masataka; Yoshimura, Rikio; Yoshikawa, Toshikazu; Sano, Hajime

    2005-01-01

    Tetrathiomolybdate (TM), a drug developed for Wilson's disease, produces an anti-angiogenic and anti-inflammatory effect by reducing systemic copper levels. TM therapy has proved effective in inhibiting the growth of tumors in animal tumor models and in cancer patients. We have hypothesized that TM may be used for the therapy of rheumatoid arthritis and have examined the efficacy of TM on adjuvant-induced arthritis in the rat, which is a model of acute inflammatory arthritis and inflammatory cachexia. TM delayed the onset of and suppressed the severity of clinical arthritis on both paw volume and the arthritis score. Histological examination demonstrated that TM significantly reduces the synovial hyperplasia and inflammatory cell invasion in joint tissues. Interestingly, TM can inhibit the expression of vascular endothelial growth factor in serum synovial tissues, especially in endothelial cells and macrophages. Moreover, the extent of pannus formation, which leads to bone destruction, is correlated with the content of vascular endothelial growth factor in the serum. There was no mortality in TM-treated rat abnormalities. TM also suppressed inflammatory cachexia. We suggest that copper deficiency induced by TM is a potent approach both to inhibit the progression of rheumatoid arthritis with minimal adverse effects and to improve the well-being of rheumatoid arthritis patients. PMID:16277669

  17. Intraoperative Radiotherapy Combined With Adjuvant Chemoradiotherapy for Locally Advanced Gastric Adenocarcinoma

    SciTech Connect

    Fu Shen; Lu Jiade; Zhang Qing Yang Zhe; Peng Lihua; Xiong, Fei

    2008-12-01

    Purpose: To evaluate the efficacy of intraoperative radiotherapy (IORT) followed by concurrent chemotherapy and external beam RT (EBRT) in the treatment of locally advanced gastric adenocarcinoma. Methods and Materials: A total of 97 consecutive and nonselected patients with newly diagnosed Stage T3, T4, or N+ adenocarcinoma of the stomach underwent gastrectomy with D2 lymph node dissection between March 2003 and October 2005. Of the 97 patients, 51 received adjuvant concurrent chemotherapy (5-fluorouracil, leucovorin, docetaxel, and cisplatin) and EBRT (EBRT group) and 46 received IORT (dose range, 12-15 Gy) immediately after gastrectomy and lymph node dissection before concurrent chemoradiotherapy (EBRT+IORT group). Results: After a median follow-up of 24 months, the 3-year locoregional control rate was 77% and 63% in the two groups with or without IORT, respectively (p = 0.05). The 3-year overall survival and disease-free survival rate was 47% and 36% in the EBRT group and 56% and 44% in the EBRT+IORT group, respectively (p > 0.05). Multivariate analyses revealed that the use of IORT, presence of residual disease after surgery, and pN category were independent prognostic factors for locoregional control and that IORT, pN, and pT categories were independent prognostic factors for overall survival (p < 0.05). Four patients experienced Grade 3 or 4 late complications, but no significant difference was observed between the two groups. Conclusions: Radical gastrectomy with D2 lymph node dissection and IORT followed by adjuvant chemoradiotherapy appeared to be feasible and well-tolerated in the treatment of locally advanced gastric cancer. The addition of IORT to the trimodality treatment significantly improved the 3-year locoregional control rate.

  18. Conjunctival Autograft Alone or Combined With Adjuvant Beta-Radiation? A Randomized Clinical Trial

    SciTech Connect

    Arruda Viani, Gustavo; Carrara Fonseca, Ellen; De Fendi, Ligia Issa; Melani Rocha, Eduardo

    2012-03-01

    Purpose: To evaluate the effectiveness and safety of postoperative low single-dose of beta-irradiation ({beta}-RT) in pterygium comparing conjunctival autograft (CAG) surgery with CAG plus adjuvant {beta}-RT in a randomized clinical trial. Methods: This trial was designed as a prospective, randomized, single-center study. Surgery was performed in all cases according to the CAG technique. One hundred and eight pterygia were postoperatively randomized to CAG + {beta}-RT or CAG alone. In the case of {beta}-RT, a (90) Sr eye applicator was used to deliver 10 Gy to the sclera surface at a dose rate of between 200 and 250 cGy/min. After treatment, both an ophthalmologist and a radiation oncologist performed the follow-up examinations. The accumulated data were analyzed using a group sequential test. Results: Between February 2008 and September 2008, 116 eyes with primary pterygium were operated on according to the trial protocol. Adjuvant treatment was performed within 24 h postoperatively. Eight patients were lost to follow-up, resulting in 108 patients who could be analyzed. At a mean follow-up of 18 months (range, 8-33), in the 54 eyes randomized to receive CAG + {beta}-RT, 5 relapses occurred compared with 12 recurrences in the 54 eyes in CAG, for a crude control rate of 90.8 % vs. 78%; p = 0.032, respectively. The treatment complications as hyperemia, total dehiscence of the autograft and dellen were significantly more frequent in the CAG (p < 0.05). The arm of {beta}-RT resulted in better cosmetic results and improves of symptoms than CAG. Conclusions: A low single-dose of {beta}-RT of 10 Gy after CAG surgery was a simple, effective, and safe treatment that reduced the risk of primary pterygium recurrence, improved symptoms after surgery, resulting in a better cosmetic effect than only CAG.

  19. The Known Immunologically Active Components of Astragalus Account for Only a Small Proportion of the Immunological Adjuvant Activity When Combined with Conjugate Vaccines

    PubMed Central

    Hong, Feng; Xiao, Weilie; Ragupathi, Govind; Lau, Clara B. S.; Leung, Ping Chung; Yeung, K. Simon; George, Constantine; Cassileth, Barrie; Kennelly, Edward; Livingston, Philip O.

    2013-01-01

    The 95% ethanol extract of Astragalus has been demonstrated to have potent activity as an immunological adjuvant when administered with vaccines of various types. We endeavor here to identify the components of this extract that are responsible for this adjuvant activity. Mice were immunized with KLH conjugated to cancer carbohydrate antigens globo H and GD3 and cancer peptide antigen MUC1 combined with different Astragalus fractions or with commercially available Astragalus saponins and flavonoids. The antibody responses against cancer antigens and KLH were quantitated in ELISA assays, and toxicity was calculated by weight loss. Astragalosides II and IV were the most active components, but the toxicity of these two differed dramatically. Astragaloside II was the most toxic Astragalus component with 5–10% weight loss at a dose of 500 µg while astragaloside IV showed no weight loss at all at this dose, suggesting that astragaloside IV might be utilized as an immunological adjuvant in future studies. Several flavonoids also had significant adjuvant activity. However, when the activities of these known immunologically active components of Astragalus (and of endotoxin) are calculated based on the extent of their presence in the 95% ethanol extract, they provide only a small proportion of the immunological activity. This raises the possibility that additional uniquely active components of Astragalus may contribute to adjuvant activity, or that the adjuvant activity of Astragalus is greater than the activity of the sum of its parts. PMID:21128203

  20. A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes

    PubMed Central

    Joseph, Sarah; Quinn, Killian; Greenwood, Aldona; Cope, Alethea V.; McKay, Paul F.; Hayes, Peter J.; Kopycinski, Jakub T.; Gilmour, Jill; Miller, Aleisha N.; Geldmacher, Christof; Nadai, Yuka; Ahmed, Mohamed I. M.; Montefiori, David C.; Dally, Len; Bouliotis, George; Lewis, David J. M.; Tatoud, Roger; Wagner, Ralf; Esteban, Mariano; Shattock, Robin J.; McCormack, Sheena; Weber, Jonathan

    2017-01-01

    There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals

  1. Optimization of route of administration for coexposure to ovalbumin and particle matter to induce adjuvant activity in respiratory allergy in the mouse.

    PubMed

    Steerenberg, P A; van Dalen, W J; Withagen, C E T; Dormans, J A M A; van Loveren, H

    2003-11-01

    Epidemiological and experimental studies have not only shown that air pollution induces increased pulmonary morbidity, and mortality, but also that air pollution components may potentiate allergic responses. The respiratory allergy model to ovalbumin in the mouse has been shown a useful tool to characterize the adjuvant potency of air pollution components. However, the choice for the most effective route of administration for testing small amounts of air pollution component is hampered by the diversity of routes of administration used. To test the adjuvant activity of airborne particles (Ottawa dust EHC-93), we studied the optimal route of respiratory administration: intranasally (in) and aerosol (aero) in comparison with responses observed by intraperitoneal (ip) with diesel exhaust particles (DEP) as a positive control. Our results show that the combination of in/aero with ovalbumin caused almost similar immunoglobulin (Ig)E and inflammatory responses compared to the ip/aero. In/in application induced less responses for IgE, less inflammation in the lung, and less increased numbers of eosinophils in the bronchoalveolar lavage (BAL). This response increased dramatically when ovalbumin was coadministered with DEP. Subsequently, EHC-93, which is made up of airborne particles, was tested via the in/in route of administration. EHC-93 induced similar IgE responses, inflammation, and eosinophilic response in BAL compared to DEP. In addition, EHC-93 increased the airway responsiveness of the ovalbumin-sensitized mice measured in unrestrained condition and not in nonsensitized control mice. It is concluded that intranasal sensitization with intranasal challenge with airborne particles (EHC-93) is an effective route of administration to show potency of adjuvant activity of airborne particles.

  2. Involvement of CD300a Phosphatidylserine Immunoreceptor in Aluminum Salt Adjuvant-Induced Th2 Responses.

    PubMed

    Miki, Haruka; Nakahashi-Oda, Chigusa; Sumida, Takayuki; Shibuya, Akira

    2015-06-01

    Aluminum salt (alum) has been widely used for vaccinations as an adjuvant. Alum not only enhances immunogenicity but also induces Th2 cell immune responses. However, the mechanisms of how alum enhances Th2 cell immune responses have been controversial. In an experimental allergic airway inflammation model, in which alum in conjunction with OVA Ag was i.p. injected for immunization, we found that apoptotic cells and inflammatory dendritic cells (iDC) expressing CD300a, an inhibitory immunoreceptor for phosphatidylserine (PS), significantly increased in number in the peritoneal cavity after the immunization. In contrast, apoptotic cells and iDCs were scarcely observed in the peritoneal cavity after injection of OVA alone. In CD300a-deficient mice, eosinophil infiltration in bronchoalveolar lavage fluid, serum IgE levels, and airway hyperreactivity were significantly decreased after immunization with alum plus OVA compared with wild-type mice. In vitro, iDCs purified from CD300a-deficient mice after the immunization induced significantly less IL-4 production from OT-II naive CD4(+) T cells after coculture with OVA Ag. CD300a expressed on iDCs bound PS on apoptotic cells in the peritoneal cavity after injection of OVA plus alum. Blocking CD300a interaction with PS by injection of a neutralizing anti-CD300a Ab resulted in inhibition of the development of allergic airway inflammation. These results suggest that CD300a is involved in alum-induced Th2 skewing. Copyright © 2015 by The American Association of Immunologists, Inc.

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

    PubMed

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

    2016-01-13

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

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

    PubMed Central

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

    2016-01-01

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

  5. A novel JAK inhibitor, peficitinib, demonstrates potent efficacy in a rat adjuvant-induced arthritis model.

    PubMed

    Ito, Misato; Yamazaki, Shunji; Yamagami, Kaoru; Kuno, Masako; Morita, Yoshiaki; Okuma, Kenji; Nakamura, Koji; Chida, Noboru; Inami, Masamichi; Inoue, Takayuki; Shirakami, Shohei; Higashi, Yasuyuki

    2017-01-01

    The Janus kinase (JAK) family of tyrosine kinases is associated with various cytokine receptors. JAK1 and JAK3 play particularly important roles in the immune response, and their inhibition is expected to provide targeted immune modulation. Several oral JAK inhibitors have recently been developed for treating autoimmune diseases, including rheumatoid arthritis (RA). Here, we investigated the pharmacological effects of peficitinib (formerly known as ASP015K), a novel, chemically synthesized JAK inhibitor. We found that peficitinib inhibited JAK1 and JAK3 with 50% inhibitory concentrations of 3.9 and 0.7 nM, respectively. Peficitinib also inhibited IL-2-dependent T cell proliferation in vitro and STAT5 phosphorylation in vitro and ex vivo. Furthermore, peficitinib dose-dependently suppressed bone destruction and paw swelling in an adjuvant-induced arthritis model in rats via prophylactic or therapeutic oral dosing regimens. Peficitinib also showed efficacy in the model by continuous intraperitoneal infusion. Area under the concentration versus time curve (AUC) at 50% inhibition of paw swelling via intraperitoneal infusion was similar to exposure levels of AUC at 50% inhibition via oral administration, implying that AUC might be important for determining the therapeutic efficacy of peficitinib. These data suggest that peficitinib has therapeutic potential for the oral treatment of RA. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  6. Nanoemulsion-based mucosal adjuvant induces apoptosis in human epithelial cells

    PubMed Central

    Orzechowska, Beata U.; Kukowska-Latallo, Jolanta F.; Coulter, Alexa D.; Szabo, Zsuzsanna; Gamian, Andrzej; Myc, Andrzej

    2015-01-01

    Nanoemulsions (NEs) are adjuvants that enhance antigen penetration of the nasal mucosa, increase cellular uptake of antigens by both epithelial and dendritic cells, and promote the migration of antigen-loaded dendritic cells to regional lymph nodes within 24-hours of vaccine administration. The objective of this study was to elucidate cell death caused by W805EC NE and identify caspases and genes associated with death pathways. Consistent with this aim, we show that exposure of human epithelial cells (EC), both RPMI 2650 and FaDu, to NE results in the activation of caspases (1, 3/7, 6, 8, and 9) and the expression of genes involved in apoptotic as well as authophagy and necrosis pathways. Interestingly, the NE activates caspase 8 which promotes “immunogenic apoptosis”. The rescue assay was employed to investigate the fate of RPMI 2650 cells treated with W805EC NE. After four hour treatment with as little as 0.03% of NE no cells were rescued at 72 hours. Remarkably, immediately after four-hour treatment, the cells morphologically resembled untreated cells and most of the cells were alive. Altogether, these results suggest that NE induces death of human ECs through multiple pathways. Epithelial cell death caused by W805EC may have further implications on antigen uptake, processing, and presentation by DC's. PMID:25817825

  7. Phase II trial of adjuvant pelvic radiation "sandwiched" between combination paclitaxel and carboplatin in women with uterine papillary serous carcinoma.

    PubMed

    Einstein, Mark H; Frimer, Marina; Kuo, Dennis Y-S; Reimers, Laura L; Mehta, Keyur; Mutyala, Subhakar; Huang, Gloria S; Hou, June Y; Goldberg, Gary L

    2012-01-01

    To evaluate the safety and survival in women treated with adjuvant pelvic radiation "sandwiched" between six cycles of paclitaxel and carboplatin chemotherapy with completely resected UPSC. Surgically staged women with UPSC (FIGO stage 1-4) and no visible residual disease were enrolled. Treatment involved paclitaxel (175 mg/m(2)) and carboplatin (AUC=6.0-7.5) every 21 days for 3 doses, followed by radiation therapy (RT), followed by an additional 3 cycles of paclitaxel and carboplatin (AUC=5-6). Survival analysis, using Kaplan-Meier methods, was performed on patients who completed at least 3 cycles of chemotherapy and RT. A total of 81 patients were enrolled, of which 72 patients completed the first 3 cycles of chemotherapy followed by prescribed RT. Median age was 67 years (range: 43-82 years). 59/72 (82%) had disease confined to the uterus and 13/72 (18%) had completely resected extra-uterine disease (stage 3 and 4). 65 (83%) completed the protocol. Overall PFS and OS for combined stage 1 and 2 patients was 65.5 ± 3.6 months and 76.5 ± 4.3 months, respectively. PFS and OS for combined stage 3 and 4 patients was 25.8 ± 3.0 and 35.9 ± 5.3 months, respectively. Three-year % survival probability for stage 1 and 2 patients was 84% and for stage 3 and 4 patients was 50%. Of the 435 chemotherapy cycles administered, there were 11(2.5%) G3/G4 non-hematologic toxicities. 26(6.0%) cycles had dose reductions and 37(8.5%) had dose delays. Compared to prior studies of single modality adjuvant therapy, RT "sandwiched" between paclitaxel and carboplatin chemotherapy is well-tolerated and highly efficacious in women with completely resected UPSC. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Prognostic impact of progesterone receptor status combined with body mass index in breast cancer patients treated with adjuvant aromatase inhibitor.

    PubMed

    Ohara, Masahiro; Akimoto, Etsushi; Noma, Midori; Matsuura, Kazuo; Doi, Mihoko; Kagawa, Naoki; Itamoto, Toshiyuki

    2015-11-01

    Aromatase inhibitors have played a central role in endocrine therapy for the treatment of estrogen receptor (ER)-positive breast cancer in postmenopausal patients. However, prognostic factors for recurrence following such treatment have not been identified. The current study aimed to validate the prognostic value of endocrine-related progesterone receptor (PgR) status combined with body mass index (BMI). Among 659 consecutive patients with primary breast cancer who underwent curative surgery between 2002 and 2012, 184 postmenopausal patients with ER-positive (ER+) and human epidermal growth factor receptor type 2-negative (HER2-) breast cancer who were treated with adjuvant aromatase inhibitor therapy were assessed. The patients were assigned to groups based on BMI, according to the WHO cut-off value: ≥25 kg/m(2) (high, H) or <25 kg/m(2) (low, L). Positive nodal status, negative PgR status, BMI-H and a high Ki-67 labeling index (≥20%) were found to be significantly associated with a short recurrence-free interval (RFI) upon univariate analysis (P=0.048, 0.007, 0.027, and 0.012, respectively). The patients were further grouped based on their combined PgR/BMI status. The RFI was significantly shorter in the PgR- and/or BMI-H group compared with that of the PgR+/BMI-L group (P=0.012). Multivariate analysis revealed PgR- tumors and/or BMI-H and positive nodal status to be independent prognostic factors (P=0.012 and 0.020, respectively). The present findings indicate that PgR/BMI status may serve as a practical tool in the management of ER+ and HER2- breast cancer in patients treated with adjuvant aromatase inhibitors.

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

    PubMed Central

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

    2006-01-01

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

  10. Involvement of pentraxin-3 in anti-neutrophil cytoplasmic antibody production induced by aluminum salt adjuvant.

    PubMed

    Nagai, Kei; Aratani, Yasuaki; Shibuya, Akira; Yamagata, Kunihiro

    2017-01-01

    Pentraxin 3 (PTX3) is a multifunctional soluble factor. PTX3 can be involved in the regulation of vasculitis and is expressed in the cytoplasm of neutrophils. As anti-neutrophil cytoplasmic antibody (ANCA) is recognised as a cause of vasculitis, we aimed to discover the role of PTX3 in ANCA production in vivo. To this end, we used aluminum salt (alum), which induces neutrophil extracellular traps, as an adjuvant for producing anti-myeloperoxidase-ANCA (MPO-ANCA). Specifically, we intraperitoneally injected alum and recombinant MPO (rMPO) into MPO-deficient mice and then measured the concentration of anti-MPO IgG in their blood. To show the involvement of extracellular PTX3 in this model, we assessed PTX3 protein content and host double-stranded DNA levels in the mice's peritoneal fluid after alum injection. In addition, we simultaneously administered recombinant PTX3, rMPO and alum to MPO-deficient mice to assess the function of PTX3 in producing anti-MPO IgG in vivo. Anti-MPO IgG was produced by the alum + rMPO immunisation model in MPO-deficient but not wildtype mice. Injection of alum induced extracellular PTX3 as well as double-stranded DNA and dead cells in MPO-deficient mice. Simultaneous injection of recombinant PTX3 with rMPO and alum attenuated the production of anti-MPO IgG in MPO-deficient mice. Our current findings provide evidence that PTX3 attenuates the production of murine MPO-ANCA.

  11. Hard-food mastication suppresses complete Freund's adjuvant-induced nociception.

    PubMed

    Ogawa, A; Morimoto, T; Hu, J W; Tsuboi, Y; Tashiro, A; Noguchi, K; Nakagawa, H; Iwata, K

    2003-01-01

    The effect of food hardness during mastication on nociceptive transmission in the spinal cord was studied by analyzing complete Freund's adjuvant (CFA) induced nocifensive behavior and Fos expression. The behavioral study showed that the shortening of the withdrawal latency following CFA injection into the hind paw was depressed after a change in the given food hardness from soft to hard. The depression of nocifensive behavior in the rats with hard food was reversed after i.v. injection of naloxone. Fos protein-like immunoreactive cells (Fos protein-LI cells) were expressed in the superficial and deep laminae of the L4-6 spinal dorsal horn after s.c. injection of CFA into the hind paw during soft food mastication. The number of Fos protein-LI cells was decreased in the rats with hard food mastication followed by soft food. This reduction of Fos protein-LI cells following change in food hardness was reversed after i.v. application of naloxone. Furthermore, the depression of Fos protein-LI cells following hard food intake was significantly inhibited after bilateral inferior alveolar nerve transection or bilateral ablation of the somatosensory cortex. These findings suggest that the change in food hardness during mastication might drive an opioid descending system through the trigeminal sensory pathway and somatosensory cortex resulting in an antinociceptive effect on chronic pain. However, IAN transection and cortical ablation did not induce 100% reversal of Fos expression, suggesting other than trigeminal sensory system may be involved in this phenomena, such as the pathway through the brainstem reticular formation.

  12. Combined Adjuvant Radiochemotherapy With IMRT/XELOX Improves Outcome With Low Renal Toxicity in Gastric Cancer

    SciTech Connect

    Boda-Heggemann, Judit; Hofheinz, Ralf-Dieter; Weiss, Christel; Mennemeyer, Philipp; Mai, Sabine K.; Hermes, Petra; Wertz, Hansjoerg; Post, Stefan; Massner, Bernd; Hieber, Udo; Hochhaus, Andreas; Wenz, Frederik; Lohr, Frank

    2009-11-15

    Objectives: Adjuvant radiochemotherapy improves survival of patients with advanced gastric cancer. We assessed in two sequential cohorts whether improved radiotherapy technique (IMRT) together with intensified chemotherapy improves outcome vs. conventional three-dimensional conformal radiotherapy (3D-CRT) and standard chemotherapy in these patients while maintaining or reducing renal toxicity. Materials and Methods: Sixty consecutive patients treated for gastric cancer either with 3D-CRT (n = 27) and IMRT (n = 33) were evaluated. More than 70% had undergone D2 resection. Although there was a slight imbalance in R0 status between cohorts, N+ status was balanced. Chemotherapy consisted predominantly of 5-fluorouracil/folinic acid (n = 36) in the earlier cohort and mostly of oxaliplatin/capecitabine (XELOX, n = 24) in the later cohort. Primary end points were overall survival (OS), disease-free survival (DFS), and renal toxicity based on creatinine levels. Results: Median follow-up (FU) of all patients in the 3D-CRT group was 18 months and in the IMRT group 22 months (median FU of surviving patients 67 months in the 3D-CRT group and 25 months in the IMRT group). Overall median survival (and DFS) were 18 (13) months in the 3D-CRT group and both not reached in the IMRT group (p = 0.0492 and 0.0216). Actuarial 2-year survival was 37% and 67% in the 3D-CRT and IMRT groups, respectively. No late renal toxicity >Grade 2 (LENT-SOMA scale) was observed in either cohort. Conclusion: When comparing sequentially treated patient cohorts with similar characteristics, OS and DFS improved with the use of IMRT and intensified chemotherapy without signs of increased renal toxicity.

  13. Inter-Clade Protection Offered by Mw-Adjuvanted Recombinant HA, NP Proteins, and M2e Peptide Combination Vaccine in Mice Correlates with Cellular Immune Response

    PubMed Central

    Ingle, Nilesh B.; Virkar, Rashmi G.; Arankalle, Vidya A.

    2017-01-01

    We documented earlier that Mw (heat-killed suspension of Mycobacterium indicus pranii) adjuvant when used with conserved antigens, nucleoprotein (NP), and ectodomain of matrix (M2) protein (M2e) provided complete protection against homologous (clade 2.2) virus challenge in mice. The present study extends these observations to inter-clade challenge (clade 2.3.2.1) H5N1 virus and attempts to understand preliminary immunologic basis for the observed protection. Female BALB/c mice immunized with a single or two doses of vaccine formulations (clade 2.2 antigens) were challenged with 100LD50 homologous or heterologous (clade 2.3.2.1) virus. To understand the preliminary immunologic mechanism, we studied proportions of selected immune cell types, immune response gene expression, and Th1/Th2 cytokines induced by antigen-stimulated splenocytes from immunized mice, at different time points. Complete protection was conferred by Mw-HA, Mw-HA + NP, and Mw-HA + NP + M2e against homologous challenge. The protection correlated with IgG2a antibody titers indicating important role of Th1 response. Despite high inter-cladal antigenic differences, complete protection against the heterologous strain was achieved with Mw-HA + NP + M2e. Of note, a single dose with higher antigen concentrations (50 µg HA + 50 μg NP + 50 μg M2e) led to 80% protection against clade 2.3.2.1 strain. The protection conferred by Mw-HNM correlated with induction of IFN-γ, CD8+ T cytotoxic cells, and CD4+ T helper cells. Mw-adjuvanted HA + NP + M2e combination represents a promising vaccine candidate deserving further evaluation. PMID:28119689

  14. Ameliorative effect of p-coumaric acid, a common dietary phenol, on adjuvant-induced arthritis in rats.

    PubMed

    Pragasam, Samuel Joshua; Murunikkara, Vachana; Sabina, Evan Prince; Rasool, MahaboobKhan

    2013-02-01

    p-Coumaric acid (3-(4-hydroxyphenyl)-2-propenoic acid), a common dietary polyphenol, is widely distributed in cereals, fruits and vegetables with antioxidant property. Numerous studies have enlightened the ability of dietary phenols to be considered as potential therapeutics against arthritis. In this study, we aimed to investigate the ameliorative effect of plant phenolic p-coumaric acid on adjuvant-induced arthritis in rats. The reference drug indomethacin was used for comparison purposes. Arthritis was induced in rats by a single intradermal injection of complete freund's adjuvant (0.1 mL) into the foot pad of right hind paw. p-Coumaric acid (100 mg/kg b wt) and indomethacin (3 mg/kg b wt) were administered intraperitoneally for 8 days from day 11 to 18 after adjuvant injection. An increase in the activities/levels of lysosomal enzymes, tissue marker enzymes, glycoproteins and paw thickness was observed in the arthritic rats, on the contrary, the body weight was found to be reduced in arthritic rats when compared to normal control rats. Administration of p-coumaric acid (100 mg/kg b wt) to the arthritic rats reverted back the altered physical and biochemical parameters to near normal levels comparable to indomethacin treatment. Histopathological evaluation of ankle joints in arthritic rats also revealed the anti-inflammatory effect of p-coumaric acid by the reduction in leukocytes infiltration. Thus, the present study clearly demonstrates the anti-inflammatory potential of the p-coumaric acid against adjuvant-induced arthritis in rats.

  15. Co-administration of adjuvants along with Moringa oleifera attenuates beryllium-induced oxidative stress and histopathological alterations in rats.

    PubMed

    Agrawal, Narottam Das; Nirala, Satendra Kumar; Shukla, Sangeeta; Mathur, Ramesh

    2015-01-01

    Moringa oleifera Lam. (Moringaceae) is a rich source of antioxidants. All parts of the plant are medicinally important and have been used as traditional medicine for a variety of human ailments in India. Therapeutic efficacy of adjuvants with M. oleifera (MO) root extract was investigated against beryllium-induced oxidative stress. Hydroalcoholic (50% v/v) root extract of M. oleifera (150 mg/kg, p.o.) alone and combinations of M. oleifera with either piperine (2.5 mg/kg, p.o.) or curcumin (5.0 mg/kg, p.o.) daily for 1 week were administered in experimental rats against beryllium toxicity (1.0 mg/kg, i.p. daily for 5 weeks). Oxidative stress parameters including blood sugar, G-6-Pase in liver, and DNA damage were analyzed. Histopathological changes in liver and kidney were also observed. Beryllium enhanced lipid peroxidation (LPO), depleted reduced glutathione (GSH) and antioxidant enzymes activities, decreased blood sugar and G-6-Pase activity, and did not damage DNA. Histologically, liver was observed with structural loss and disintegration of hepatocytes, heavy vacuolation in hepatocytes, and kidney was observed with constriction of glomeruli and hypertrophy in epithelial cells of uriniferous tubules. Therapy of M. oleifera with piperine was effective; however, combination of M. oleifera with curcumin showed better therapeutic effect by reduction of LPO, elevated GSH level, maintained antioxidant enzymes activities, restored blood sugar, and G-6-Pase activity in liver together with almost normal histoarchitecture of liver and kidney. Curcumin enhanced therapeutic efficacy of M. oleifera root extract and showed better antioxidant potential against beryllium toxicity.

  16. 15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats

    PubMed Central

    Kawahito, Yutaka; Kondo, Motoharu; Tsubouchi, Yasunori; Hashiramoto, Akira; Bishop-Bailey, David; Inoue, Ken-ichiro; Kohno, Masataka; Yamada, Ryoji; Hla, Timothy; Sano, Hajime

    2000-01-01

    Peroxisome proliferator–activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-γ agonists are also negative regulators of macrophage activation and have modulatory effects on tumorigenesis. In this study we demonstrate that synovial tissue localized expression of PPAR-γ in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-γ in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-γ by 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and the synthetic PPAR-γ ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-γ ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ2 were more potent than troglitazone. These findings suggest that PPAR-γ may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ2, may be useful in the treatment of RA. PMID:10903334

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

    PubMed

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

    2016-06-01

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

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

    PubMed Central

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

    2016-01-01

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

  19. Methanolic extract of Ruta graveolens L. inhibits inflammation and oxidative stress in adjuvant induced model of arthritis in rats.

    PubMed

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

    2009-04-01

    Ruta graveolens L. (Rutaceae) are traditionally used for the treatment of rheumatism, arthritis and other inflammatory conditions in the traditional medicine of India. The purpose of this study was to investigate anti-inflammatory and anti-oxidant effects of methanolic extract of Ruta graveolens L. in adjuvant induced arthritis in rats. Methanolic extract of Ruta graveolens (MER) exhibited maximum percentage of oedema inhibition at a dose of 20 mg/kg on 21st day of adjuvant arthritis. The effect was higher than that of standard drug indomethacin. The activities of cycloxygenase-2 and myeloperoxidase and concentration of thiobarbituric acid reactive substance (TBARS) were decreased and the activities of antioxidant enzymes, vitamins C & E and reduced glutathione level were increased on treatment with MER. The increment in ESR and total WBC, reduction in RBC count and haemoglobin and aberrant changes to the C-reactive protein (CRP) and ceruloplasmin levels observed in the arthritic animals were also found to be significantly restored in MER treated rats. Histopathology of paw tissue showed decreased oedema formation and cellular infiltration on supplementation with MER. Thus the results demonstrated the potential beneficiary effect of methanolic extract of Ruta graveolens on adjuvant induced arthritis in rats.

  20. Combining viral vectored and protein-in-adjuvant vaccines against the blood-stage malaria antigen AMA1: report on a phase 1a clinical trial.

    PubMed

    Hodgson, Susanne H; Choudhary, Prateek; Elias, Sean C; Milne, Kathryn H; Rampling, Thomas W; Biswas, Sumi; Poulton, Ian D; Miura, Kazutoyo; Douglas, Alexander D; Alanine, Daniel Gw; Illingworth, Joseph J; de Cassan, Simone C; Zhu, Daming; Nicosia, Alfredo; Long, Carole A; Moyle, Sarah; Berrie, Eleanor; Lawrie, Alison M; Wu, Yimin; Ellis, Ruth D; Hill, Adrian V S; Draper, Simon J

    2014-12-01

    The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines--chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising "mixed-modality" regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible.

  1. Combining Viral Vectored and Protein-in-adjuvant Vaccines Against the Blood-stage Malaria Antigen AMA1: Report on a Phase 1a Clinical Trial

    PubMed Central

    Hodgson, Susanne H; Choudhary, Prateek; Elias, Sean C; Milne, Kathryn H; Rampling, Thomas W; Biswas, Sumi; Poulton, Ian D; Miura, Kazutoyo; Douglas, Alexander D; Alanine, Daniel GW; Illingworth, Joseph J; de Cassan, Simone C; Zhu, Daming; Nicosia, Alfredo; Long, Carole A; Moyle, Sarah; Berrie, Eleanor; Lawrie, Alison M; Wu, Yimin; Ellis, Ruth D; Hill, Adrian V S; Draper, Simon J

    2014-01-01

    The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines—chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising “mixed-modality” regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible. PMID:25156127

  2. [The sick building syndrome as a part of 'ASIA' (autoimmune/auto-inflammatory syndrome induced by adjuvants)].

    PubMed

    Maoz-Segal, Ramit; Agmon-Levin, Nancy; Israeli, Eitan; Shoenfeld, Yehuda

    2015-02-01

    The entity 'sick building syndrome' is poorly defined and comprises of a set of symptoms resulting from environmental exposure to a work or a living environment. The symptoms are mainly "allergic"-like and include nasal, eye, and mucous membrane irritation, dry skin as well as respiratory symptoms and general symptoms such as fatigue, lethargy, headaches and fever. The Autoimmune [Auto-inflammatory] Syndrome Induced by Adjuvants (ASIA) is a wider term which describes the role of various environmental factors in the pathogenesis of immune mediated diseases. Factors entailing an immune adjuvant activity such as infectious agents, silicone, aluminium salts and others were found in association with defined and non-defined immune mediated diseases. The sick building syndrome and ASIA share a similar complex of signs and symptoms and probably the same immunological mechanisms which further support a common denominator.

  3. Advax-Adjuvanted Recombinant Protective Antigen Provides Protection against Inhalational Anthrax That Is Further Enhanced by Addition of Murabutide Adjuvant

    PubMed Central

    Feinen, Brandon; Petrovsky, Nikolai; Verma, Anita

    2014-01-01

    Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy. PMID:24554695

  4. Advax-adjuvanted recombinant protective antigen provides protection against inhalational anthrax that is further enhanced by addition of murabutide adjuvant.

    PubMed

    Feinen, Brandon; Petrovsky, Nikolai; Verma, Anita; Merkel, Tod J

    2014-04-01

    Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy.

  5. Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats.

    PubMed

    Ikuta, Hiroyuki; Kawase, Atsushi; Iwaki, Masahiro

    2017-03-01

    2-Arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drugs are commonly used in racemic mixtures (rac) for clinical use. 2-APA undergoes unidirectional chiral inversion of the in vivo inactive R-enantiomer to the active S-enantiomer. Inflammation causes the reduction of metabolic activities of drug-metabolizing enzymes such as cytochrome P450 (P450) and UDP-glucuronosyltransferase. However, it is unclear whether inflammation affects the stereoselective pharmacokinetics and chiral inversion of 2-APA such as ibuprofen (IB). We examined the effects of inflammation on the pharmacokinetics of R-IB and S-IB after intravenous administration of rac-IB, R-IB, and S-IB to adjuvant-induced arthritic (AA) rats, an animal model of inflammation. The plasma protein binding of rac-IB, glucuronidation activities for R-IB and S-IB, and P450 contents of liver microsomes in AA rats were determined. Total clearance (CLtot) of IB significantly increased in AA rats, although the glucuronidation activities for IB, and P450 contents of liver microsomes decreased in AA rats. We presumed that the increased CLtot of IB in AA rats was caused by the elevated plasma unbound fraction of IB due to decreased plasma albumin levels in AA rats. Notably, CLtot of R-IB but not S-IB significantly increased in AA rats after intravenous administration of rac-IB. These results suggested that AA could affect drug efficacies after stereoselective changes in the pharmacokinetics of R-IB and S-IB.

  6. TLR4 and TLR7/8 Adjuvant Combinations Generate Different Vaccine Antigen-Specific Immune Outcomes in Minipigs when Administered via the ID or IN Routes

    PubMed Central

    McKay, Paul F.; King, Deborah F. L.; Mann, Jamie F. S.; Barinaga, Guillermo; Carter, Darrick; Shattock, Robin J.

    2016-01-01

    The induction of high levels of systemic and mucosal humoral immunity is a key goal for many prophylactic vaccines. However, adjuvant strategies developed in mice have often performed poorly in the clinic. Due to their closer similarity to humans, minipigs may provide a more accurate picture of adjuvant performance. Based on their complementary signalling pathways, we assessed humoral immune responses to model antigens after co-administration with the toll-like receptor 4 (TLR4) stimulator glucopyranosyl lipid adjuvant (GLA-AF) or the TLR7/8 agonist resiquimod (R848) (alone and in combination) via the intradermal (ID), intranasal (IN) or combined routes in the Gottingen minipig animal model. Surprisingly, we discovered that while GLA-AF additively enhanced the adjuvant effect of R848 when injected ID, it abrogated the adjuvant activity of R848 after IN inoculation. We then performed a route comparison study using a CN54 gp140 HIV Envelope model antigen adjuvanted with R848 + GLA-AF (ID) or R848 alone (IN). Animals receiving priming inoculations via one route were then boosted by the alternate route. Although differences were observed in the priming phase (IN or ID), responses converged upon boosting by the alternative route with no observable impact resultant from the order of administration (ID/IN vs IN/ID). Specific IgG responses were measured at a distal mucosal site (vaginal), although there was no evidence of mucosal linkage as these closely reflected serum antibody levels. These data indicate that the complex in vivo cross-talk between innate pathways are likely tissue specific and cannot be predicted by simple in vitro models. PMID:26862758

  7. TLR4 and TLR7/8 Adjuvant Combinations Generate Different Vaccine Antigen-Specific Immune Outcomes in Minipigs when Administered via the ID or IN Routes.

    PubMed

    McKay, Paul F; King, Deborah F L; Mann, Jamie F S; Barinaga, Guillermo; Carter, Darrick; Shattock, Robin J

    2016-01-01

    The induction of high levels of systemic and mucosal humoral immunity is a key goal for many prophylactic vaccines. However, adjuvant strategies developed in mice have often performed poorly in the clinic. Due to their closer similarity to humans, minipigs may provide a more accurate picture of adjuvant performance. Based on their complementary signalling pathways, we assessed humoral immune responses to model antigens after co-administration with the toll-like receptor 4 (TLR4) stimulator glucopyranosyl lipid adjuvant (GLA-AF) or the TLR7/8 agonist resiquimod (R848) (alone and in combination) via the intradermal (ID), intranasal (IN) or combined routes in the Gottingen minipig animal model. Surprisingly, we discovered that while GLA-AF additively enhanced the adjuvant effect of R848 when injected ID, it abrogated the adjuvant activity of R848 after IN inoculation. We then performed a route comparison study using a CN54 gp140 HIV Envelope model antigen adjuvanted with R848 + GLA-AF (ID) or R848 alone (IN). Animals receiving priming inoculations via one route were then boosted by the alternate route. Although differences were observed in the priming phase (IN or ID), responses converged upon boosting by the alternative route with no observable impact resultant from the order of administration (ID/IN vs IN/ID). Specific IgG responses were measured at a distal mucosal site (vaginal), although there was no evidence of mucosal linkage as these closely reflected serum antibody levels. These data indicate that the complex in vivo cross-talk between innate pathways are likely tissue specific and cannot be predicted by simple in vitro models.

  8. Cissus quadrangularis attenuates the adjuvant induced arthritis by down regulating pro-inflammatory cytokine and inhibiting angiogenesis.

    PubMed

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

    2015-12-04

    In traditional medicine, Cissus quadrangularis has been used as a chief ingredient of many formulation for the treatment of inflammatory and bone disorders.. The study was carried out to investigate the anti-arthritic activity of C. quadrangularis hydroalcoholic extract (CQHE) and to explore the plausible mechanism of action. Arthritis was induced by sub plantar administration of formaldehyde (2% v/v) and 0.1ml of complete Freund's adjuvant. Joint swelling was measured on days 8, 9 and 10 in formaldehyde-induced arthritis and on 3, 7, 14 and 21 days in adjuvant induced arthritis (AIA) respectively. Serum and ankle joints of AIA rats were used for estimation of serum TNF-α level, oxidative stress markers and synovial expression of proinflammatory cytokines/cytokine receptor (IL-1β, IL-6, TNF-R1), angiogenesis marker (VEGF) and matrix metalloproteinases (MMP-3& 9). An acute and 28-day oral toxicity was carried out to evaluate the safety of the test drug. CQHE produced a dose dependent inhibition of joint swelling in both formaldehyde-induced and adjuvant induced arthritis. CQHE treatment also reduced serum TNF-α level, oxidative stress and synovial expression of inflammatory and angiogenesis marker. In sub acute toxicity study of CQHE, chronic administration of CQHE did not produce any physiological and pathological changes as compared to normal rats. Our study demonstrated the anti-arthritic potential of C. quadrangularis and it validates its traditional use for the treatment of arthritis and other inflammatory disorders. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Glucocorticoids improve endothelial function in rheumatoid arthritis: a study in rats with adjuvant-induced arthritis.

    PubMed

    Verhoeven, F; Totoson, P; Maguin-Gaté, K; Prigent-Tessier, A; Marie, C; Wendling, D; Moretto, J; Prati, C; Demougeot, C

    2017-05-01

    To determine the effect of glucocorticoids (GCs) on endothelial dysfunction (ED) and on traditional cardiovascular (CV) risk factors in the adjuvant-induced arthritis (AIA) rat model. At the first signs of AIA, a high dose (HD) [10 mg/kg/day, intraperitoneally (i.p.), GC-HD] or low dose (LD) (1 mg/kg/day, i.p., GC-LD) of prednisolone was administered for 3 weeks. Endothelial function was studied in aortic rings relaxed with acetylcholine (Ach) with or without inhibitors of nitric oxide synthase (NOS), cyclooxygenase 2 (COX-2), arginase, endothelium derived hyperpolarizing factor (EDHF) and superoxide anions ( O2-°) production. Aortic expression of endothelial NOS (eNOS), Ser1177-phospho-eNOS, COX-2, arginase-2, p22(phox) and p47(phox) was evaluated by Western blotting analysis. Arthritis scores, blood pressure, heart rate and blood levels of cytokines, triglycerides, cholesterol and glucose were measured. GC-HD but not GC-LD reduced arthritis score significantly and improved Ach-induced relaxation (P < 0·05). The positive effect of GC-HD resulted from increased NOS activity and EDHF production and decreased COX-2/arginase activities and O2-° production. These functional effects relied upon increased phospho-eNOS expression and decreased COX-2, arginase-2 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression. Despite the lack of effect of GC-LD on ED, it increased NOS and EDHF and down-regulated O2-° pathways but did not change arginase and COX-2 pathways. GC-HD increased triglycerides levels and blood pressure significantly (P < 0·05). Both doses of GCs decreased to the same extent as plasma interleukin (IL)-1β and tumour necrosis factor (TNF)-α levels (P < 0·05). Our data demonstrated that subchronic treatment with prednisolone improved endothelial function in AIA via pleiotropic effects on endothelial pathways. These effects occurred independently of the deleterious cardiometabolic effects and the impact of prednisolone on

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

    PubMed

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

    2016-04-06

    Aiming to enhance the immunogenicity of subunit vaccines, a novel antigen delivery and adjuvant system based on dopamine polymerization on the surface of poly(D,L-lactic-glycolic-acid) nanoparticles (NPs) with multiple mechanisms of immunity enhancement is developed. The mussel-inspired biomimetic polydopamine (pD) not only serves as a coating to NPs but also functionalizes NP surfaces. The method is facile and mild including simple incubation of the preformed NPs in the weak alkaline dopamine solution, and incorporation of hepatitis B surface antigen and TLR9 agonist unmethylated cytosine-guanine (CpG) motif with the pD surface. The as-constructed NPs possess pathogen-mimicking manners owing to their size, shape, and surface molecular immune-activating properties given by CpG. The biocompatibility and biosafety of these pathogen-mimicking NPs are confirmed using bone marrow-derived dendritic cells. Pathogen-mimicking NPs hold great potential as vaccine delivery and adjuvant system due to their ability to: 1) enhance cytokine secretion and immune cell recruitment at the injection site; 2) significantly activate and maturate dendritic cells; 3) induce stronger humoral and cellular immune responses in vivo. Furthermore, this simple and versatile dopamine polymerization method can be applicable to endow NPs with characteristics to mimic pathogen structure and function, and manipulate NPs for the generation of efficacious vaccine adjuvants. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    PubMed Central

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

    2012-01-01

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

  12. Trypanosoma cruzi adjuvants potentiate T cell-mediated immunity induced by a NY-ESO-1 based antitumor vaccine.

    PubMed

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

    2012-01-01

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

  13. Combination of the Cationic Surfactant Dimethyl Dioctadecyl Ammonium Bromide and Synthetic Mycobacterial Cord Factor as an Efficient Adjuvant for Tuberculosis Subunit Vaccines

    PubMed Central

    Holten-Andersen, L.; Doherty, T. M.; Korsholm, K. S.; Andersen, P.

    2004-01-01

    Recombinant, immunodominant antigens derived from Mycobacterium tuberculosis can be used to effectively vaccinate against subsequent infection. However, the efficacy of these recombinant proteins is dependent on the adjuvant used for their delivery. This problem affects many potential vaccines, not just those for tuberculosis, so the discovery of adjuvants that can promote the development of cell-mediated immunity is of great interest. We have previously shown that the combination of the cationic surfactant dimethyl dioctadecyl ammonium bromide and the immunomodulator modified lipid A synergistically potentiates Th1 T-cell responses. Here we report a screening program for other adjuvants with reported Th1-promoting activity and identify a second novel adjuvant formulation that drives the development of Th1 responses with an extremely high efficacy. The combination of dimethyl dioctadecyl ammonium bromide and the synthetic cord factor trehalose dibehenate promotes strong protective immune responses, without overt toxicity, against M. tuberculosis infection in a vaccination model and thus appears to be a very promising candidate for the development of human vaccines. PMID:14977968

  14. Different Adjuvants Induce Common Innate Pathways That Are Associated with Enhanced Adaptive Responses against a Model Antigen in Humans

    PubMed Central

    Burny, Wivine; Callegaro, Andrea; Bechtold, Viviane; Clement, Frédéric; Delhaye, Sophie; Fissette, Laurence; Janssens, Michel; Leroux-Roels, Geert; Marchant, Arnaud; van den Berg, Robert A.; Garçon, Nathalie; van der Most, Robbert; Didierlaurent, Arnaud M.

    2017-01-01

    To elucidate the role of innate responses in vaccine immunogenicity, we compared early responses to hepatitis B virus (HBV) surface antigen (HBsAg) combined with different Adjuvant Systems (AS) in healthy HBV-naïve adults, and included these parameters in multi-parametric models of adaptive responses. A total of 291 participants aged 18–45 years were randomized 1:1:1:1:1 to receive HBsAg with AS01B, AS01E, AS03, AS04, or Alum/Al(OH)3 at days 0 and 30 (ClinicalTrials.gov: NCT00805389). Blood protein, cellular, and mRNA innate responses were assessed at early time-points and up to 7 days after vaccination, and used with reactogenicity symptoms in linear regression analyses evaluating their correlation with HBs-specific CD4+ T-cell and antibody responses at day 44. All AS induced transient innate responses, including interleukin (IL)-6 and C-reactive protein (CRP), mostly peaking at 24 h post-vaccination and subsiding to baseline within 1–3 days. After the second but not the first injection, median interferon (IFN)-γ levels were increased in the AS01B group, and IFN-γ-inducible protein-10 levels and IFN-inducible genes upregulated in the AS01 and AS03 groups. No distinct marker or signature was specific to one particular AS. Innate profiles were comparable between AS01B, AS01E, and AS03 groups, and between AS04 and Alum groups. AS group rankings within adaptive and innate response levels and reactogenicity prevalence were similar (AS01B ≥ AS01E > AS03 > AS04 > Alum), suggesting an association between magnitudes of inflammatory and vaccine responses. Modeling revealed associations between adaptive responses and specific traits of the innate response post-dose 2 (activation of the IFN-signaling pathway, CRP and IL-6 responses). In conclusion, the ability of AS01 and AS03 to enhance adaptive responses to co-administered HBsAg is likely linked to their capacity to activate innate immunity, particularly the IFN-signaling pathway. PMID

  15. Neoadjuvant and adjuvant chemotherapy combined with anatomical resection of feline injection-site sarcoma: results in 21 cats.

    PubMed

    Bray, J; Polton, G

    2016-06-01

    This study assesses the outcome of two combined treatment strategies for the treatment of feline injection-site sarcoma (FISS). Twenty-one cats with primary or recurrent FISS received 3 cycles of neoadjuvant chemotherapy with epirubicin (25 mg m(-2) ), then an anatomical resection of the entire muscle compartment containing the tumour was performed based on the findings of co-axial imaging. Cats then received a further 3 cycles of adjuvant chemotherapy. Follow-up was performed by telephone contact with a median follow-up time of 1072 days. Three cats (14%) developed local tumour recurrence at days 264, 664 and 1573 after surgery. A median survival time could not be calculated as over 80% of the study population remained alive or were censored due to death from other causes. When compared to historical controls, the results of this study demonstrate superior rates of tumour-free survival and disease-free interval.

  16. Archaeosome Vaccine Adjuvants Induce Strong Humoral, Cell-Mediated, and Memory Responses: Comparison to Conventional Liposomes and Alum†

    PubMed Central

    Krishnan, Lakshmi; Dicaire, Chantal J.; Patel, Girishchandra B.; Sprott, G. Dennis

    2000-01-01

    Ether glycerolipids extracted from various archaeobacteria were formulated into liposomes (archaeosomes) possessing strong adjuvant properties. Mice of varying genetic backgrounds, immunized by different parenteral routes with bovine serum albumin (BSA) entrapped in archaeosomes (∼200-nm vesicles), demonstrated markedly enhanced serum anti-BSA antibody titers. These titers were often comparable to those achieved with Freund's adjuvant and considerably more than those with alum or conventional liposomes (phosphatidylcholine-phosphatidylglycerol-cholesterol, 1.8:0.2:1.5 molar ratio). Furthermore, antigen-specific immunoglobulin G1 (IgG1), IgG2a, and IgG2b isotype antibodies were all induced. Association of BSA with the lipid vesicles was required for induction of a strong response, and >80% of the protein was internalized within most archaeosome types, suggesting efficient release of antigen in vivo. Encapsulation of ovalbumin and hen egg lysozyme within archaeosomes showed similar immune responses. Antigen-archaeosome immunizations also induced a strong cell-mediated immune response: antigen-dependent proliferation and substantial production of cytokines gamma interferon (Th1) and interleukin-4 (IL-4) (Th2) by spleen cells in vitro. In contrast, conventional liposomes induced little cell-mediated immunity, whereas alum stimulated only an IL-4 response. In contrast to alum and Freund's adjuvant, archaeosomes composed of Thermoplasma acidophilum lipids evoked a dramatic memory antibody response to the encapsulated protein (at ∼300 days) after only two initial immunizations (days 0 and 14). This correlated with increased antigen-specific cell cycling of CD4+ T cells: increase in synthetic (S) and mitotic (G2/M) and decrease in resting (G1) phases. Thus, archaeosomes may be potent vaccine carriers capable of facilitating strong primary and memory humoral, and cell-mediated immune responses to the entrapped antigen. PMID:10603368

  17. Giant Petrous Bone Cholesteatoma: Combined Microscopic Surgery and an Adjuvant Endoscopic Approach.

    PubMed

    Iannella, Giannicola; Savastano, Ersilia; Pasquariello, Benedetta; Re, Massimo; Magliulo, Giuseppe

    2016-03-01

    Petrous bone cholesteatomas (PBCs) are epidermoid cysts, which have developed in the petrous portion of the temporal bone and may be congenital or acquired. Cholesteatomas arising in this region have a tendency to invade bone and functional structures and the middle and posterior fossae reaching an extensive size. Traditionally, surgery of a giant PBC contemplates lateral transtemporal or middle fossa microscopic surgery; however, in recent years, endoscopic surgical techniques (primary or complementary endoscopic approach) are starting to receive a greater consensus for middle ear and mastoid surgeries. We report the rare case of an 83-year-old Caucasian male affected by a giant cholesteatoma that eroded the labyrinth and the posterior fossa dura and extended to the infralabyrinthine region, going beyond the theca and reaching the first cervical vertebra. The giant cholesteatoma was managed through a combined approach (microscopic and, subsequently, complementary endoscopic approach). In this case report, we illustrate some advantages of this surgical choice.

  18. Giant Petrous Bone Cholesteatoma: Combined Microscopic Surgery and an Adjuvant Endoscopic Approach

    PubMed Central

    Iannella, Giannicola; Savastano, Ersilia; Pasquariello, Benedetta; Re, Massimo; Magliulo, Giuseppe

    2016-01-01

    Petrous bone cholesteatomas (PBCs) are epidermoid cysts, which have developed in the petrous portion of the temporal bone and may be congenital or acquired. Cholesteatomas arising in this region have a tendency to invade bone and functional structures and the middle and posterior fossae reaching an extensive size. Traditionally, surgery of a giant PBC contemplates lateral transtemporal or middle fossa microscopic surgery; however, in recent years, endoscopic surgical techniques (primary or complementary endoscopic approach) are starting to receive a greater consensus for middle ear and mastoid surgeries. We report the rare case of an 83-year-old Caucasian male affected by a giant cholesteatoma that eroded the labyrinth and the posterior fossa dura and extended to the infralabyrinthine region, going beyond the theca and reaching the first cervical vertebra. The giant cholesteatoma was managed through a combined approach (microscopic and, subsequently, complementary endoscopic approach). In this case report, we illustrate some advantages of this surgical choice. PMID:26937334

  19. Surfactin inducing mitochondria-dependent ROS to activate MAPKs, NF-κB and inflammasomes in macrophages for adjuvant activity.

    PubMed

    Gan, Ping; Gao, Zhenqiu; Zhao, Xiuyun; Qi, Gaofu

    2016-12-14

    Surfactin, a natural lipopeptide, can be used both as parenteral and non-parenteral adjuvant for eliciting immune response. However, the mechanisms that confer its adjuvant properties have not been fully explored. By staining with NHS-Rhodamine B labeled surfactin and Mito-Tracker Green, we found surfactin could penetrate into macrophages to bind with mitochondria, following induce ROS that could be inhibited by mitochondria-dependent ROS inhibitor. ROS enhanced p38 MAPK and JNK expression, as well their phorsphorylation, following activated NF-κB nuclear translocation in macrophages that was obviously inhibited by mitochondria-dependent ROS inhibitor. However, inhibition of ROS production only weakened p38 MAPK and JNK expression, but not their phosphorylation in macrophages. As a result, surfaction could activate NF-κB to release TNF-α by the mitochondria-dependent ROS signalling pathway. ROS also induced macrophages apoptosis to release endogenous danger signals, following activated inflammasomes of NLRP1, NLRP3, IPAF and AIM2 in vitro and only NLRP1 in vivo, as well caspase-1 and IL-1 in macrophages, which were significantly inhibited by pre-treatment with ROS inhibitors. Collectively, surfactin as a kind of non-pathogen-associated molecular patterns, modulates host innate immunity by multiple signalling pathways, including induction of mitochondria-dependent ROS, activating MAPKs and NF-κB, and inducing cell apoptosis to realease endogenous danger signals for activation of inflammasomes.

  20. Surfactin inducing mitochondria-dependent ROS to activate MAPKs, NF-κB and inflammasomes in macrophages for adjuvant activity

    PubMed Central

    Gan, Ping; Gao, Zhenqiu; Zhao, Xiuyun; Qi, Gaofu

    2016-01-01

    Surfactin, a natural lipopeptide, can be used both as parenteral and non-parenteral adjuvant for eliciting immune response. However, the mechanisms that confer its adjuvant properties have not been fully explored. By staining with NHS-Rhodamine B labeled surfactin and Mito-Tracker Green, we found surfactin could penetrate into macrophages to bind with mitochondria, following induce ROS that could be inhibited by mitochondria-dependent ROS inhibitor. ROS enhanced p38 MAPK and JNK expression, as well their phorsphorylation, following activated NF-κB nuclear translocation in macrophages that was obviously inhibited by mitochondria-dependent ROS inhibitor. However, inhibition of ROS production only weakened p38 MAPK and JNK expression, but not their phosphorylation in macrophages. As a result, surfaction could activate NF-κB to release TNF-α by the mitochondria-dependent ROS signalling pathway. ROS also induced macrophages apoptosis to release endogenous danger signals, following activated inflammasomes of NLRP1, NLRP3, IPAF and AIM2 in vitro and only NLRP1 in vivo, as well caspase-1 and IL-1 in macrophages, which were significantly inhibited by pre-treatment with ROS inhibitors. Collectively, surfactin as a kind of non-pathogen-associated molecular patterns, modulates host innate immunity by multiple signalling pathways, including induction of mitochondria-dependent ROS, activating MAPKs and NF-κB, and inducing cell apoptosis to realease endogenous danger signals for activation of inflammasomes. PMID:27966632

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

    PubMed

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

    2014-10-01

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

  2. Triple combination as adjuvant to cryotherapy in the treatment of solar lentigines: investigator-blinded, randomized clinical trial.

    PubMed

    Hexsel, D; Hexsel, C; Porto, M D; Siega, C

    2015-01-01

    Post-inflammatory hyperpigmentation is a frequent concern when treating solar lentigines. To assess the safety and efficacy of a triple combination cream with fluocinolone acetonide 0.01%, hydroquinone 4% and tretinoin 0.05% as adjuvant to cryotherapy in the treatment of solar lentigines in hands dorsum, and in the prevention of post-inflammatory hyperpigmentation after cryotherapy. This prospective, randomized, controlled, investigator-blinded, single-centre study enrolled 50 patients. Twenty-five patients received a 2-week daily triple combination cream plus sunscreen pre-treatment and 25 received sunscreen alone. After that, cryotherapy was performed in all patients followed by a 3-week recovery period. After this period, patients received the same initial treatment and were followed up for 8 weeks. Melanin and erythema levels of a target and a control lentigo were objectively measured using a narrowband reflectance spectrophotometer. Lentigines count, colour homogeneity and global improvement were also assessed. The number of solar lentigines reduced in the first 2 weeks only in patients who used the triple combination 25 ± 7 vs. 22 ± 8 (P < 0.0001), and reduced at the end of the study for both groups (P < 0.0001). The melanin levels also reduced in the first 2 weeks only in patients who used the triple combination 297 ± 69 vs. 273 ± 66 (P < 0.0001) and reduced at the end of the study for both groups (P < 0.0001). Erythema and residual blisters from cryotherapy were the reported adverse reactions. Triple combination cream can be used to enhance the resolution of solar lentigines, and to significantly reduce melanin levels and lentigines count, improving treatment results. It was well-tolerated and did not increase the occurrence of neither erythema nor other side-effects after the cryotherapy. © 2014 European Academy of Dermatology and Venereology.

  3. Complete Freund's adjuvant induces experimental autoimmune myocarditis by enhancing IL-6 production during initiation of the immune response.

    PubMed

    Fontes, Jillian A; Barin, Jobert G; Talor, Monica V; Stickel, Natalie; Schaub, Julie; Rose, Noel R; Čiháková, Daniela

    2017-06-01

    Complete Freund's Adjuvant (CFA) emulsified with an antigen is a widely used method to induce autoimmune disease in animal models, yet the contribution of CFA to the immune response is not well understood. We compared the effectiveness of CFA with Incomplete Freund's Adjuvant (IFA) or TiterMax Gold Adjuvant (TMax) in experimental autoimmune myocarditis (EAM) in male mice. EAM was induced in A/J, BALB/c, and IL6KO BALB/c male mice by injection of the myocarditogenic peptide in CFA, IFA, or TMax on days 0 and 7. EAM severity was analyzed by histology on day 21. In addition, specific flow cytometry outcomes were evaluated on day 21. Only mice immunized with CFA and myocarditogenic peptide on both days 0 and 7 developed substantial myocarditis as measured by histology. We observed a significantly increased level of IL6 in the spleen 3 days after CFA immunization. In the spleen and heart on day 21, there was an expansion of myeloid cells in CFA-immunized mice, as compared to IFA or TMax-immunized animals. Recombinant IL-6 at the time of IFA immunization partially restored susceptibility of the mice to EAM. We also treated EAM-resistant IL-6 knockout mice with recombinant IL-6 around the time of the first immunization, on days -1 to 2, completely restoring disease susceptibility, showing that the requirement for IL-6 coincides with primary immunization. Examining APC populations in the lymph node draining the immunization site evidenced the contribution of IL-6 to the CFA-dependence of EAM was through controlling local dendritic cell (DC) trafficking. CFA used with myocarditogenic peptide twice is required to induce EAM in both A/J and Balb/c mice. Although IFA and TiterMax induce antibody responses, only CFA preferentially induced autoantigen-specific responses. CFA expands monocytes in the heart and in the spleen. IL-6 signaling is required during short window around primary immunization to induce EAM. In addition, IL-6 deficient mice resistance to EAM could be

  4. Complete Freund's adjuvant induces experimental autoimmune myocarditis by enhancing IL‐6 production during initiation of the immune response

    PubMed Central

    Fontes, Jillian A.; Barin, Jobert G.; Talor, Monica V.; Stickel, Natalie; Schaub, Julie; Rose, Noel R.

    2017-01-01

    Abstract Introduction Complete Freund's Adjuvant (CFA) emulsified with an antigen is a widely used method to induce autoimmune disease in animal models, yet the contribution of CFA to the immune response is not well understood. We compared the effectiveness of CFA with Incomplete Freund's Adjuvant (IFA) or TiterMax Gold Adjuvant (TMax) in experimental autoimmune myocarditis (EAM) in male mice. Methods EAM was induced in A/J, BALB/c, and IL6KO BALB/c male mice by injection of the myocarditogenic peptide in CFA, IFA, or TMax on days 0 and 7. EAM severity was analyzed by histology on day 21. In addition, specific flow cytometry outcomes were evaluated on day 21. Results Only mice immunized with CFA and myocarditogenic peptide on both days 0 and 7 developed substantial myocarditis as measured by histology. We observed a significantly increased level of IL6 in the spleen 3 days after CFA immunization. In the spleen and heart on day 21, there was an expansion of myeloid cells in CFA‐immunized mice, as compared to IFA or TMax‐immunized animals. Recombinant IL‐6 at the time of IFA immunization partially restored susceptibility of the mice to EAM. We also treated EAM‐resistant IL‐6 knockout mice with recombinant IL‐6 around the time of the first immunization, on days −1 to 2, completely restoring disease susceptibility, showing that the requirement for IL‐6 coincides with primary immunization. Examining APC populations in the lymph node draining the immunization site evidenced the contribution of IL‐6 to the CFA‐dependence of EAM was through controlling local dendritic cell (DC) trafficking. Conclusions CFA used with myocarditogenic peptide twice is required to induce EAM in both A/J and Balb/c mice. Although IFA and TiterMax induce antibody responses, only CFA preferentially induced autoantigen‐specific responses. CFA expands monocytes in the heart and in the spleen. IL‐6 signaling is required during short window around primary immunization to

  5. The importance of adjuvant formulation in the development of a TB vaccine

    PubMed Central

    Baldwin, Susan L.; Bertholet, Sylvie; Reese, Valerie A.; Ching, Lance K.; Reed, Steven G.; Coler, Rhea N.

    2011-01-01

    An effective protein based vaccine for tuberculosis (TB) will require a safe and effective adjuvant. There are few adjuvants in approved human vaccines, including Alum and the oil-in-water (o/w) based emulsions MF59 (Novartis Vaccines and Diagnostics), AS03 and AS04 (GlaxoSmith Kline Biologics, GSK) AF03 (Sanofi), and liposomes (Crucell). When used with pure, defined proteins, both Alum and emulsion adjuvants are effective at inducing primarily humoral responses. One of the newest adjuvants in approved products is AS04, which combines monophosphoryl lipid A (MPL), a TLR-4 agonist, with Alum. In this study, we compared two adjuvants, an o/w emulsion (SE), and an o/w emulsion incorporating glucopyranosyl lipid adjuvant (GLA), a synthetic TLR-4 agonist, together with a recombinant protein, ID93. Both the emulsion SE and GLA-SE adjuvants induce potent cellular responses in combination with ID93 in mice. ID93/SE induced Th2 biased immune responses, whereas ID93/GLA-SE induced multifunctional CD4+ Th1 cell responses (IFN-γ, TNF-α and IL-2). The ID93/GLA-SE vaccine candidate induced significant protection in mice and guinea pigs, whereas no protection was observed with ID93/SE, as assessed by reductions in bacterial burden, survival, and pathology. These results highlight the importance of properly formulating subunit vaccines with effective adjuvants for use against TB. PMID:22291184

  6. The importance of adjuvant formulation in the development of a tuberculosis vaccine.

    PubMed

    Baldwin, Susan L; Bertholet, Sylvie; Reese, Valerie A; Ching, Lance K; Reed, Steven G; Coler, Rhea N

    2012-03-01

    An effective protein-based vaccine for tuberculosis will require a safe and effective adjuvant. There are few adjuvants in approved human vaccines, including alum and the oil-in-water-based emulsions MF59 (Novartis Vaccines and Diagnostics), AS03 and AS04 (GlaxoSmithKline Biologics), AF03 (Sanofi), and liposomes (Crucell). When used with pure, defined proteins, both alum and emulsion adjuvants are effective at inducing primarily humoral responses. One of the newest adjuvants in approved products is AS04, which combines monophosphoryl lipid A, a TLR-4 agonist, with alum. In this study, we compared two adjuvants: a stable oil-in-water emulsion (SE) and a stable oil-in-water emulsion incorporating glucopyranosyl lipid adjuvant, a synthetic TLR-4 agonist (GLA-SE), each together with a recombinant protein, ID93. Both the emulsion SE and GLA-SE adjuvants induce potent cellular responses in combination with ID93 in mice. ID93/SE induced Th2-biased immune responses, whereas ID93/GLA-SE induced multifunctional CD4(+) Th1 cell responses (IFN-γ, TNF-α, and IL-2). The ID93/GLA-SE vaccine candidate induced significant protection in mice and guinea pigs, whereas no protection was observed with ID93/SE, as assessed by reductions in bacterial burden, survival, and pathology. These results highlight the importance of properly formulating subunit vaccines with effective adjuvants for use against tuberculosis.

  7. Antioxidant and angiostatic effect of Spirulina platensis suspension in complete Freund's adjuvant-induced arthritis in rats.

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Gupta, Mradu; Sasmal, Saumyakanti; Mukherjee, Arup

    2014-01-01

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

  10. Huo-Luo-Xiao-Ling Dan modulates antigen-directed immune response in adjuvant-induced inflammation

    PubMed Central

    Rajaiah, Rajesh; Lee, David Y.-W.; Ma, Zhongze; Fan, Arthur Y.; Lao, Lixing; Fong, Harry HS; Berman, Brian M.; Moudgil, Kamal D.

    2010-01-01

    Ethnopharmacological relevance HLXL is a traditional Chinese medicine that has long been used in folk medicine for the treatment of chronic inflammatory diseases. However, the precise immunological mechanisms by which HLXL mediates its anti-inflammatory activity are not fully defined. Aim of the study To determine the effects of HLXL on antigen-specific immune parameters in adjuvant-induced inflammation model in the Lewis rat. Materials and Methods Rats were fed daily with either HLXL (2.3 g/kg) or vehicle (water) beginning 3 d before subcutaneous injection of heat-killed M. tuberculosis H37Ra (Mtb), and then continued for another 6 d. After 9 d of Mtb injection, the draining lymph node cells were tested for T cell proliferative and cytokine responses against mycobacterial heat-shock protein 65 (Bhsp65). Moreover, sera were tested for anti-Bhsp65 antibodies and nitric oxide (NO). Results HLXL-treated rats showed reduced T cell proliferative response to Bhsp65 compared to control rats. Furthermore, HLXL suppressed IL-17 response but enhanced IL-10 response without much effect on IFN-γ. HLXL treatment also reduced the levels of anti-Bhsp65 antibodies but not that of NO. Conclusions HLXL feeding modulated both the cellular and the humoral immune response to Bhsp65 favoring an anti-inflammatory milieu for suppression of adjuvant-induced inflammation. PMID:19429337

  11. Old and new adjuvants.

    PubMed

    McKee, Amy S; Marrack, Philippa

    2017-07-19

    Adjuvants have been deliberately added to vaccines since the 1920's when alum was discovered to boost antibody responses, leading to better protection. The first adjuvants were discovered by accident and were used in the safer but less immunogenic subunit vaccines, supposedly by providing an antigen depot to extend antigen presentation. Since that time, much has been discovered about how these adjuvants impact cells at the tissue site to activate innate immune responses, mobilize dendritic cells and drive adaptive immunity. New approaches to vaccine construction for infectious diseases that have so far not been well addressed by conventional vaccines often attempt to induce antibodies, polyfunctional CD4(+) T cells and CD8(+) CTLs. The discovery of pattern recognition receptors and ligands that drive desired T cell responses has led to development of novel adjuvant strategies using immunomodulatory agents to direct appropriate immune responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Calcium Phosphate Nanoparticle Adjuvant

    PubMed Central

    He, Qing; Mitchell, Alaina R.; Johnson, Stacy L.; Wagner-Bartak, Claus; Morcol, Tulin; Bell, Steve J. D.

    2000-01-01

    Vaccination to protect against human infectious diseases may be enhanced by using adjuvants that can selectively stimulate immunoregulatory responses. In a murine model, a novel nanoparticulate adjuvant composed of calcium phosphate (CAP) was compared with the commonly used aluminum (alum) adjuvants for its ability to induce immunity to herpes simplex virus type 2 (HSV-2) and Epstein-Barr virus (EBV) infections. Results indicated that CAP was more potent as an adjuvant than alum, elicited little or no inflammation at the site of administration, induced high titers of immunoglobulin G2a (IgG2a) antibody and neutralizing antibody, and facilitated a high percentage of protection against HSV-2 infection. Additional benefits of CAP include (i) an insignificant IgE response, which is an important advantage over injection of alum compounds, and (ii) the fact that CAP is a natural constituent of the human body. Thus, CAP is very well tolerated and absorbed. These studies were performed with animal models. By virtue of the potency of this CAP adjuvant and the relative absence of side effects, we believe that this new CAP formulation has great potential for use as an adjuvant in humans. PMID:11063495

  13. Late toxicities and outcomes of adjuvant radiotherapy combined with concurrent bevacizumab in patients with triple-negative non-metastatic breast cancer

    PubMed Central

    Pernin, V; Belin, L; Cottu, P; Bontemps, P; Lemanski, C; De La Lande, B; Baumann, P; Missohou, F; Levy, C; Peignaux, K; Reynaud-Bougnoux, A; Denis, F; Gobillion, A; Bollet, M; Vago, N A; Dendale, R; Campana, F; Fourquet, A

    2015-01-01

    Objective: To evaluate the safety of the concurrent combination of bevacizumab with adjuvant radiotherapy (B-RT) in breast cancer (BC). Methods: Multicentre, prospective study, of the toxicity of adjuvant radiotherapy (RT) alone or B-RT in patients with non-metastatic BC enrolled in randomized Phase 3 BEATRICE trial. Early and late toxicities were assessed by the Common Terminology Criteria for Adverse Events v. 3.0 during and 12 months after the completion of RT. Results: From 2007 to 2012, 39 females received adjuvant B-RT and 45 received adjuvant RT alone. Median follow-up was 21.5 months. All patients had triple-negative non-metastatic BC and received adjuvant chemotherapy followed by RT. 90% of the 39 females treated by concurrent B-RT received whole breast irradiation (WBI) with a boost and 4 (10%) received post-mastectomy RT. Lymph node RT was delivered in 49% of the females with internal mammary chain irradiation. The mean duration of bevacizumab was 11.7 months. 38 (84%) females treated by RT alone received WBI with a boost and 16% of the females received post-mastectomy RT. Lymph node RT was delivered in 47% of the females with internal mammary chain RT in 31%. Grade 3 acute dermatitis was observed in 9% of patients receiving B-RT and 5% of patients receiving RT alone with no significant difference. 1 year after the completion of RT, the most common late grade 1–2 toxicities in the B-RT group were pain (18%), fibrosis (8%) and telangiectasia (5%). Conclusion: The concurrent bevacizumab with locoregional RT is associated with acceptable early and late 1-year toxicities in patients with BC. Advances in knowledge: The largest series of this association. PMID:25645108

  14. Late toxicities and outcomes of adjuvant radiotherapy combined with concurrent bevacizumab in patients with triple-negative non-metastatic breast cancer.

    PubMed

    Pernin, V; Belin, L; Cottu, P; Bontemps, P; Lemanski, C; De La Lande, B; Baumann, P; Missohou, F; Levy, C; Peignaux, K; Reynaud-Bougnoux, A; Denis, F; Gobillion, A; Bollet, M; Vago, N A; Dendale, R; Campana, F; Fourquet, A; Kirova, Y M

    2015-04-01

    To evaluate the safety of the concurrent combination of bevacizumab with adjuvant radiotherapy (B-RT) in breast cancer (BC). Multicentre, prospective study, of the toxicity of adjuvant radiotherapy (RT) alone or B-RT in patients with non-metastatic BC enrolled in randomized Phase 3 BEATRICE trial. Early and late toxicities were assessed by the Common Terminology Criteria for Adverse Events v. 3.0 during and 12 months after the completion of RT. From 2007 to 2012, 39 females received adjuvant B-RT and 45 received adjuvant RT alone. Median follow-up was 21.5 months. All patients had triple-negative non-metastatic BC and received adjuvant chemotherapy followed by RT. 90% of the 39 females treated by concurrent B-RT received whole breast irradiation (WBI) with a boost and 4 (10%) received post-mastectomy RT. Lymph node RT was delivered in 49% of the females with internal mammary chain irradiation. The mean duration of bevacizumab was 11.7 months. 38 (84%) females treated by RT alone received WBI with a boost and 16% of the females received post-mastectomy RT. Lymph node RT was delivered in 47% of the females with internal mammary chain RT in 31%. Grade 3 acute dermatitis was observed in 9% of patients receiving B-RT and 5% of patients receiving RT alone with no significant difference. 1 year after the completion of RT, the most common late grade 1-2 toxicities in the B-RT group were pain (18%), fibrosis (8%) and telangiectasia (5%). The concurrent bevacizumab with locoregional RT is associated with acceptable early and late 1-year toxicities in patients with BC. The largest series of this association.

  15. An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity Against Diverse Fungal Pathogens

    PubMed Central

    Robbins, Nicole; Spitzer, Michaela; Yu, Tennison; Cerone, Robert P.; Averette, Anna K.; Bahn, Yong-Sun; Heitman, Joseph; Sheppard, Donald C.; Tyers, Mike; Wright, Gerard D.

    2015-01-01

    SUMMARY There is an urgent need to identify new treatments for fungal infections. By combining sub-lethal concentrations of the known antifungals fluconazole, caspofungin, amphotericin B, terbinafine, benomyl and cyprodinil with ~3600 compounds in diverse fungal species, we generated a deep reservoir of chemical-chemical interactions termed the Antifungal Combinations Matrix (ACM). Follow-up susceptibility testing against a fluconazole resistant isolate of C. albicans unveiled ACM combinations capable of potentiating fluconazole in this clinical strain. We used chemical genetics to elucidate the mode-of-action of the antimycobacterial drug clofazimine, a compound with unreported antifungal activity that synergized with several antifungals. Clofazimine induces a cell membrane stress for which the Pkc1 signaling pathway is required for tolerance. Further tests against additional fungal pathogens, including Aspergillus fumigatus, highlighted that clofazimine exhibits efficacy as a combination agent against multiple fungi. Thus, the ACM is a rich reservoir of chemical combinations with therapeutic potential against diverse fungal pathogens. PMID:26549450

  16. Evaluation of locally induced osteoarthritis by the complete and incomplete Freund's adjuvant in mice. The application of DEXA measurements.

    PubMed

    Włodarski, K H; Dickson, G R

    2002-01-01

    The inflammatory reactions elicited in mice by subcutaneous injections of IFA and CFA had opposite effects when tested on local metacarpal shank bones and the distal epiphysis of shank bones. Although the intensity of the immune reactions was similar, IFA induced bone loss, while CFA induced bone formation, which was mostly periosteal in nature. BMC and BMD measurements were assessed by means of high resolution DEXA, using a hologic 4500A bone scanner with software dedicated for the analysis of small animal bones. DEXA scans were evaluated and related to histological and bone ash content analyses. The morphological and quantitative ash weight analyses of bones exposed to the adjuvants were consistent with DEXA bone density scan measurements.

  17. A novel hepatitis B vaccine containing Advax™, a polysaccharide adjuvant derived from delta inulin, induces robust humoral and cellular immunity with minimal reactogenicity in preclinical testing

    PubMed Central

    Saade, Fadi; Honda-Okubo, Yoshikazu; Trec, Samay; Petrovsky, Nikolai

    2013-01-01

    Although current HBV vaccines have an outstanding record of safety and efficacy, reduced immunogenicity is a problem in those of older age, or having renal impairment or diabetes mellitus. In this study, we tested the ability of Advax™ adjuvant, a novel polysaccharide adjuvant based on delta inulin, to enhance the immunogenicity of hepatitis B surface antigen (HBs) in mice and guinea pigs by comparison to the traditional alum adjuvant. Advax™ provided antigen-sparing and significantly enhanced both anti-HBs antibody titers and anti-HBs CD4 and CD8 T-cells, with increases in Th1, Th2 and Th17 cytokine responses. Unlike alum, the adjuvant effect of Advax™ was seen even when injected 24 hours before the HBs antigen. Advax™ adjuvant similarly enhanced humoral and cellular immune responses in guinea pigs to a third generation preS-HBs antigen. Inclusion Advax™ adjuvant when combined with HBs antigen could provide enhanced protection over current generation HBV vaccines for immunization of low responder populations. PMID:23306367

  18. A novel hepatitis B vaccine containing Advax™, a polysaccharide adjuvant derived from delta inulin, induces robust humoral and cellular immunity with minimal reactogenicity in preclinical testing.

    PubMed

    Saade, Fadi; Honda-Okubo, Yoshikazu; Trec, Samay; Petrovsky, Nikolai

    2013-04-08

    Although current HBV vaccines have an outstanding record of safety and efficacy, reduced immunogenicity is a problem in those of older age, or having renal impairment or diabetes mellitus. In this study, we tested the ability of Advax™ adjuvant, a novel polysaccharide adjuvant based on delta inulin, to enhance the immunogenicity of hepatitis B surface antigen (HBs) in mice and guinea pigs by comparison to the traditional alum adjuvant. Advax™ provided antigen-sparing, significantly enhanced both anti-HBs antibody titers, and anti-HBs CD4 and CD8 T-cells, with increases in Th1, Th2 and Th17 cytokine responses. Unlike alum, the adjuvant effect of Advax™ was seen even when injected 24h before the HBs antigen. Advax™ adjuvant similarly enhanced humoral and cellular immune responses in guinea pigs to a third generation preS-HBs antigen. Advax™ adjuvant when combined with HBs antigen could provide enhanced protection over current generation HBV vaccines for immunization of low responder populations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Adjuvants for Vaccines to Drugs of Abuse and Addiction

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2014-09-22

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

  1. Molecular and cellular response profiles induced by the TLR4 agonist-based adjuvant Glucopyranosyl Lipid A.

    PubMed

    Lambert, Stacie L; Yang, Chin-Fen; Liu, Zheng; Sweetwood, Rosemary; Zhao, Jackie; Cheng, Lily; Jin, Hong; Woo, Jennifer

    2012-01-01

    Toll-like receptor (TLR)4 agonists are known potent immunostimulatory compounds. These compounds can be formulated as part of novel adjuvants to enhance vaccine medicated immune responses. However, the contribution of the formulation to the innate in vivo activity of TLR4 agonist compounds is not well understood. We evaluated synthetic TLR4 agonist Glucopyranosyl Lipid A (GLA) for its effects on molecular and cellular innate immune responses in the murine model. Microarray techniques were used to compare the responses to GLA in an aqueous formulation or in an oil-in-water Stable Emulsion formulation (GLA-SE) versus either SE alone or the mineral salt aluminum hydroxide (alum) at the muscle injection site over multiple timepoints. In contrast to the minimal gene upregulation induced by SE and alum, both GLA and GLA-SE triggered MyD88- and TRIF-dependent gene expression. Genes for chemokines, cytokine receptors, signaling molecules, complement, and antigen presentation were also strongly upregulated by GLA and GLA-SE. These included chemokines for T(H)1-type T cells (CXCL9 and CXCL10) and mononuclear leukocytes (CCL2, CCL3) among others. GLA-SE induced stronger and more sustained gene upregulation than GLA in the muscle; GLA-SE induced genes were also detected in local draining lymph nodes and at lower levels in peripheral blood. Both GLA and GLA-SE resulted in increased cellular trafficking to the draining lymph nodes and upregulated MHC molecules and ICAM1 on local dendritic cells. GLA and GLA-SE transiently upregulated circulating MCP-1, TNFα, IFNγ and IP-10 in blood. While GLA and GLA-SE activate a large number of shared innate genes and proteins, GLA-SE induces a quantitatively and qualitatively stronger response than GLA, SE or alum. The genes and proteins upregulated could be used to facilitate selection of appropriate adjuvant doses in vaccine formulations.

  2. Evaluation of three experimental bovine viral diarrhea virus killed vaccines adjuvanted with combinations of Quil A cholesterol and dimethyldioctadecylammonium (DDA) bromide.

    PubMed

    Ridpath, Julia F; Dominowski, Paul; Mannan, Ramasany; Yancey, Robert; Jackson, James A; Taylor, Lucas; Mediratta, Sangita; Eversole, Robert; Mackenzie, Charles D; Neill, John D

    2010-12-01

    Bovine viral diarrhea virus (BVDV) infections cause respiratory, reproductive, and enteric disease in cattle. Vaccination raises herd resistance and limits the spread of BVDV among cattle. Both killed and modified live vaccines against BVDV are available. While modified live vaccines elicit an immune response with a broader range and a longer duration of immunity, killed vaccines are considered to be safer. One way to improve the performance of killed vaccines is to develop new adjuvants. The goal of this research was evaluate new adjuvants, consisting of combinations of Quil A cholesterol and dimethyldioctadecylammonium (DDA) bromide, for use in killed vaccines. Responses to three novel killed vaccines, using combinations of Quil A and DDA as adjuvants, were compared to responses to a commercial modified live and a commercial killed vaccine. Vaccination response was monitored by measuring viral neutralizing antibodies (VN) levels and by response to challenge. All three novel vaccines were efficacious based on reduction in virus isolation, pyrexia, and depression. Compared to a commercial killed vaccine, the three novel vaccines elicited higher VN levels and reduced injection site inflammation.

  3. Irritant and adjuvant effects of gaseous formaldehyde on the ovalbumin-induced hyperresponsiveness and inflammation in a rat model.

    PubMed

    Qiao, Y; Li, B; Yang, G; Yao, H; Yang, J; Liu, D; Yan, Y; Sigsgaard, T; Yang, X

    2009-12-01

    Formaldehyde (FA) is a common indoor air pollutant that can cause asthma in people experiencing long-term exposure. While FA and other man-made chemicals contribute to the stimulation of asthma in the general population, the underlying molecular pathogenesis of this relationship is not yet well understood. To explore FA as an irritant for the onset of asthma and as an adjuvant for the induction of allergy. In the present study, 40 Wistar rats in five experimental groups were exposed to: (i) saline; (ii) ovalbumin (OVA); (iii) OVA + FA at 417 ppb; (iv) OVA + FA at 2500 ppb; and (v) FA at 2500 ppb. Current and prior occupational exposure limits in China were established at 417 ppb and 2500 ppb, respectively. Gaseous FA was administrated to the animals for 6 h/day before and during OVA immunization or saline treatment. Measured outcomes included in situ lung function analysis, cytokine measurement, and histological changes in the rat lungs. The airway reactivity, lung histological changes, pulmonary interleukin-4 secretion, and eosinophil infiltration in the OVA and FA exposed rats were significantly higher after gaseous FA exposures of 417 and 2500 ppb. While FA exposure alone did not induce significant structural changes to the airway, and the rate of inflammatory cell infiltration was the same as for the control group, pulmonary levels of interferon-gamma were significantly elevated in the exposed rats. FA may be an irritant as well as serve as an adjuvant for the onset of asthma or asthma-like symptoms.

  4. Arthritis in Lewis rats induced by the non-immunogenic adjuvant CP20961: an immunohistochemical analysis of the developing disease.

    PubMed Central

    Meacock, S C; Brandon, D R; Billingham, M E

    1994-01-01

    OBJECTIVES--The role of lymphocytes and macrophages in developing adjuvant arthritis induced by an injection of CP20961 in inbred Lewis rats was studied over a 32 day period using a novel biotin-avidin immunoperoxidase histochemical technique. METHODS--Fresh frozen sections of hind paws and spleens, as well as lymph nodes draining the site of the injected adjuvant were immunostained using a panel of monoclonal antibodies specific for subsets of lymphocytes and macrophages and for MHC Class II antigen. RESULTS--An increase in the numbers of activated T-lymphocytes was detected early in the draining lymph nodes before hind paw swelling had begun. The presence of these cells in significant numbers was only observed in the vicinity of the joint after joint swelling and damage had begun. Macrophages were among the first cells to invade the swollen paws and later were found with T-lymphocytes and cells bearing the MHC class II antigen at the face of eroding and re-organising bone. CONCLUSIONS--The activity of T-lymphocytes in initiating arthritis appeared to occur early in lymph nodes. Joint destruction was more closely associated with the arrival of macrophages but later arrival of T-lymphocytes may have contributed to the maintenance of chronic inflammation. Images PMID:7979577

  5. Antioxidant effects of Genkwa flos flavonoids on Freund׳s adjuvant-induced rheumatoid arthritis in rats.

    PubMed

    Zhang, Chun-Feng; Zhang, Su-Li; He, Xin; Yang, Xiao-Lin; Wu, Hai-Tao; Lin, Bao-Qin; Jiang, Cui-Ping; Wang, Jun; Yu, Chun-Hao; Yang, Zhong-Lin; Wang, Chong-Zhi; Li, Ping; Yuan, Chun-Su

    2014-05-14

    Genkwa flos (Daphne genkwa Sieb. et Zucc.), a Chinese herbal medicine, has been traditionally used for over two thousand years in China for inflammation related symptoms, including joint pain. To evaluate the antioxidative effects of flavonoid aglycones (FA) isolated from Genkwa flos on adjuvant arthritis in rats and to identify the relationship between antioxidant potential and whole blood viscosity (WBV). FA compounds were identified using LC-MS and the content was assayed by HPLC. Arthritis was induced by an intradermal injection of Freund׳s complete adjuvant in the footpad. The effects of FA on paw volumes, secondary arthritis scores, histopathology of joints, and body and organ weights were measured. The antioxidant effects of FA and WBV were determined. LC-MS analysis showed that the FA contained four major compounds: luteolin, apigenin, hydroxygenkwanin and genkwanin. FA significantly decreased paw edema, arthritis scores, and weight loss. These observations were consistent with the reduction of oxidative stress and the improvement of the WBV. FA significantly decreased arthritis in a rat model through antioxidant and hemorheological modulatory mechanisms. The Genkwa flos flavonoids may have clinical potential for the treatment of rheumatoid arthritis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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

    PubMed

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

    2016-09-03

    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.

  7. Comparative Adjuvant Effects of Type II Heat-Labile Enterotoxins in Combination with Two Different Candidate Ricin Toxin Vaccine Antigens.

    PubMed

    Vance, David J; Greene, Christopher J; Rong, Yinghui; Mandell, Lorrie M; Connell, Terry D; Mantis, Nicholas J

    2015-12-01

    Type II heat-labile enterotoxins (HLTs) constitute a promising set of adjuvants that have been shown to enhance humoral and cellular immune responses when coadministered with an array of different proteins, including several pathogen-associated antigens. However, the adjuvant activities of the four best-studied HLTs, LT-IIa, LT-IIb, LT-IIb(T13I), and LT-IIc, have never been compared side by side. We therefore conducted immunization studies in which LT-IIa, LT-IIb, LT-IIb(T13I), and LT-IIc were coadministered by the intradermal route to mice with two clinically relevant protein subunit vaccine antigens derived from the enzymatic A subunit (RTA) of ricin toxin, RiVax and RVEc. The HLTs were tested with low and high doses of antigen and were assessed for their abilities to stimulate antigen-specific serum IgG titers, ricin toxin-neutralizing activity (TNA), and protective immunity. We found that all four HLTs tested were effective adjuvants when coadministered with RiVax or RVEc. LT-IIa was of particular interest because as little as 0.03 μg when coadministered with RiVax or RVEc proved effective at augmenting ricin toxin-specific serum antibody titers with nominal evidence of local inflammation. Collectively, these results justify the need for further studies into the mechanism(s) underlying LT-IIa adjuvant activity, with the long-term goal of evaluating LT-IIa's activity in humans.

  8. Archaeosome Adjuvant Overcomes Tolerance to Tumor-Associated Melanoma Antigens Inducing Protective CD8+ T Cell Responses

    PubMed Central

    Krishnan, Lakshmi; Deschatelets, Lise; Stark, Felicity C.; Gurnani, Komal; Sprott, G. Dennis

    2010-01-01

    Vesicles comprised of the ether glycerolipids of the archaeon Methanobrevibacter smithii (archaeosomes) are potent adjuvants for evoking CD8+ T cell responses. We therefore explored the ability of archaeosomes to overcome immunologic tolerance to self-antigens. Priming and boosting of mice with archaeosome-antigen evoked comparable CD8+ T cell response and tumor protection to an alternate boosting strategy utilizing live bacterial vectors for antigen delivery. Vaccination with melanoma antigenic peptides TRP181-189 and Gp10025-33 delivered in archaeosomes resulted in IFN-γ producing antigen-specific CD8+ T cells with strong cytolytic capability and protection against subcutaneous B16 melanoma. Targeting responses against multiple antigens afforded prolonged median survival against melanoma challenge. Entrapment of multiple peptides within the same vesicle or admixed formulations were both effective at evoking CD8+ T cells against each antigen. Melanoma-antigen archaeosome formulations also afforded therapeutic protection against established B16 tumors when combined with depletion of T-regulatory cells. Overall, we demonstrate that archaeosome adjuvants constitute an effective choice for formulating cancer vaccines. PMID:21318177

  9. [Study on antiinflammatory effect of different chemotype of Cinnamomum camphora on rat arthritis model induced by Freund's adjuvant].

    PubMed

    Li, Hongmei; Huang, Luqi; Zhou, Aixiang; Li, Xiaoqin; Sun, Jianhui

    2009-12-01

    To study the antiinflammatory effects of naphtha from different chemotypes of Cinnamomum camphora and natural borneol on the rat arthritis model induced by Freund's adjuvant. The arthritis model was induced by injecting Freund's adjuvant in rat voix pedis dermis and the rats were randomly divided into seven groups: normal control group, model control group, triptergium wilfordii control group, borneol chemotype naphtha group, camphor chemotype naphtha group, isocamphane chemotype naphtha group and natural borneol group. Rats of the triptergium wilfordii control group were given orally 8.1 mg x kg(-1) triptergium wilfordii for 35 days, rats of the normal control group and model control group were given same volume water, and rats of other groups were given 80 mg x kg(-1) corresponding drug. We observed the rat common condition, weighed the rat body weight weekly, measured the degree of swelling of voix pedis every 4 days, weighed the thymus and spleen on the end of life, and measured the contents of cell factor TNF-alpha, IL-2, and IL-6 in rat blood serum. As far as the arthrosis degree of swelling and the contents of cell factor TNF-alpha, IL-2, IL-6 were concerned, rats of model control group were higher than normal control group, and rats of other drug groups were lower than the model control group. The order of inhibition ratios of the arthrosis degree of swelling from high to low principle was isocamphane chemotype naphtha group, camphor chemotype naphtha group, borneol chemotype naphtha group and natural borneol group. All medication administration teams evidently reduced the contents of the IL-2 and IL-6, and the inhibition ratios were higher than 38%. In the case of the contents of TNF-alpha and IL-2, all groups were not evidently different. In the case of inhibition of IL-6, camphor chemotype naphtha group was better than borneol chemotype naphtha group and natural borneol group, the latter was better than isocamphane chemotype naphtha group. As far as the

  10. Angiotensin II type 2 receptor correlates with therapeutic effects of losartan in rats with adjuvant-induced arthritis.

    PubMed

    Wang, Di; Hu, Shanshan; Zhu, Jie; Yuan, Jun; Wu, Jingjing; Zhou, Aiwu; Wu, Yujing; Zhao, Wendi; Huang, Qiong; Chang, Yan; Wang, Qingtong; Sun, Wuyi; Wei, Wei

    2013-12-01

    The angiotensin II type 1 receptor (AT1R) blocker losartan ameliorates rheumatoid arthritis (RA) in an experimental model. In RA, AT2R mainly opposes AT1R, but the mechanism by which this occurs still remains obscure. In the present study, we investigated the role of AT2R in the treatment of rats with adjuvant-induced arthritis (AIA) by losartan. Adjuvant-induced arthritis rats were treated with losartan (5, 10 and 15 mg/kg) and methotrexate (MTX; 0.5 mg/kg) in vivo from day 14 to day 28. Arthritis was evaluated by the arthritis index and histological examination. Angiotensin II, tumour necrosis factor-α, and VEGF levels were examined by ELISA. The expression of AT1R and AT2R was detected by western blot and immunohistochemistry analysis. After stimulation with interleukin-1β in vitro, the effects of the AT2R agonist CGP42112 (10(-8) -10(-5)  M) on the chemotaxis of monocytes induced by 10% foetal calf serum (FCS) were analysed by using Transwell assay. Subsequently, the therapeutic effects of CGP42112 (5, 10 and 20 μg/kg) were evaluated in vivo by intra-articular injection in AIA rats. After treatment with losartan, the down-regulation of AT1R expression and up-regulation of AT2R expression in the spleen and synovium of AIA rats correlated positively with reduction in the polyarthritis index. Treatment with CGP42112 inhibited the chemotaxis of AIA monocytes in vitro, possibly because of the up-regulation of AT2R expression. Intra-articular injection with CGP42112 (10 and 20 μg/kg) ameliorated the arthritis index and histological signs of arthritis. In summary, the present study strongly suggests that the up-regulation of AT2R might be an additional mechanism by which losartan exerts its therapeutic effects in AIA rats.

  11. Enhanced anti-rheumatic activity of methotrexate-entrapped ultradeformable liposomal gel in adjuvant-induced arthritis rat model.

    PubMed

    Zeb, Alam; Qureshi, Omer Salman; Yu, Chan-Hee; Akram, Muhammad; Kim, Hyung-Seo; Kim, Myung-Sic; Kang, Jong-Ho; Majid, Arshad; Chang, Sun-Young; Bae, Ok-Nam; Kim, Jin-Ki

    2017-06-15

    The aim of this study is to investigate in vivo anti-rheumatic activity of methotrexate-entrapped ultradeformable liposomal gel (MTX-UDLs-gel) in adjuvant-induced arthritis rat model. Methotrexate-entrapped ultradeformable liposomes (MTX-UDLs) with the optimal phosphatidylcholine to Tween 80 ratio (7:3, w/w) were incorporated into 1% Carbopol gel. MTX-UDLs-gel was characterized in terms of appearance, clarity, homogeneity, pH and drug content. The permeation of MTX-UDLs-gel across rat skin was investigated using Franz diffusion cell. In vivo anti-rheumatic activity of MTX-UDLs-gel was assessed in terms of edema volume, paw edema and leukocyte infiltration scores, histopathological analysis and inflammatory cytokines level in complete Freund's adjuvant (CFA)-induced arthritis rat model. MTX-UDLs-gel showed good homogeneity and clarity, neutral pH and about 99.5% drug content. The cumulative amount of MTX permeated for 24h from MTX-UDLs-gel (164.6μg) was 1.5 and 2.15 times higher than that of MTX-CLs-gel (113.3μg) and MTX-plain-gel (76.6μg), respectively. MTX-UDLs-gel significantly alleviated the severity of inflammation by reducing edema volume, histological scores and accumulation of neutrophils and improving tissue architecture in CFA-induced arthritis rat model. MTX-UDLs-gel effectively suppressed the expression of pro-inflammatory cytokines, TNF-α and IL-1β, in paw tissues. In conclusion, the developed MTX-UDLs-gel has a great potential for effective delivery of MTX into the inflamed joints in rheumatoid arthritis. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. The choice of adjuvant determines the cytokine profile of T cells in proteoglycan-induced arthritis but does not influence disease severity.

    PubMed

    Stoop, Jeroen N; Tibbitt, Christopher A; van Eden, Willem; Robinson, John H; Hilkens, Catharien M U

    2013-01-01

    Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic inflammation of the synovial joints. Collagen-induced arthritis (CIA) and proteoglycan-induced arthritis (PGIA) are mouse models of inflammatory arthritis; CIA is a T helper type 17 (Th17) -dependent disease that is induced with antigen in complete Freund's adjuvant, whereas PGIA is Th1-mediated and is induced using antigen in dimethyldioctadecyl-ammonium bromide (DDA) as an adjuvant. To investigate whether the type of adjuvant determines the cytokine profile of the pathogenic T cells, we have compared the effect of CFA and DDA on T-cell responses in a single arthritis model. No differences in incidence or disease severity between aggrecan-T-cell receptor transgenic mice immunized with aggrecan in either CFA or DDA were observed. Immunization with CFA resulted in a higher proportion of Th17 cells, whereas DDA induced more Th1 cells. However, the levels of interleukin-17 (IL-17) produced by T cells isolated from CFA-immunized mice after antigen-specific stimulation were not significantly different from those found in DDA-immunized mice, indicating that the increased proportion of Th17 cells did not result in significantly higher ex vivo IL-17 levels. Hence, the choice of adjuvant can affect the overall proportions of Th1 and Th17 cells, without necessarily affecting the level of cytokine production or disease incidence and severity. © 2012 Blackwell Publishing Ltd.

  13. Entomopathogenic Nematodes Combined with Adjuvants Presents a New Potential Biological Control Method for Managing the Wheat Stem Sawfly, Cephus cinctus (Hymenoptera: Cephidae).

    PubMed

    Portman, Scott L; Krishnankutty, Sindhu M; Reddy, Gadi V P

    2016-01-01

    The wheat stem sawfly, (Cephus cinctus Norton) Hymenoptera: Cephidae, has been a major pest of winter wheat and barley in the northern Great Plains for more than 100 years. The insect's cryptic nature and lack of safe chemical control options make the wheat stem sawfly (WSS) difficult to manage; thus, biological control offers the best hope for sustainable management of WSS. Entomopathogenic nematodes (EPNs) have been used successfully against other above-ground insect pests, and adding adjuvants to sprays containing EPNs has been shown to improve their effectiveness. We tested the hypothesis that adding chemical adjuvants to sprays containing EPNs will increase the ability of EPNs to enter wheat stems and kill diapausing WSS larvae. This is the first study to test the ability of EPNs to infect the WSS, C. cinctus, and test EPNs combined with adjuvants against C. cinctus in both the laboratory and the field. Infection assays showed that three different species of EPNs caused 60-100% mortality to WSS larvae. Adding Penterra, Silwet L-77, Sunspray 11N, or Syl-Tac to solutions containing EPNs resulted in higher WSS mortality than solutions made with water alone. Field tests showed that sprays containing S. feltiae added to 0.1% Penterra increased WSS mortality up to 29.1%. These results indicate a novel control method for WSS, and represent a significant advancement in the biological control of this persistent insect pest.

  14. Entomopathogenic Nematodes Combined with Adjuvants Presents a New Potential Biological Control Method for Managing the Wheat Stem Sawfly, Cephus cinctus (Hymenoptera: Cephidae)

    PubMed Central

    Portman, Scott L.; Krishnankutty, Sindhu M.

    2016-01-01

    The wheat stem sawfly, (Cephus cinctus Norton) Hymenoptera: Cephidae, has been a major pest of winter wheat and barley in the northern Great Plains for more than 100 years. The insect’s cryptic nature and lack of safe chemical control options make the wheat stem sawfly (WSS) difficult to manage; thus, biological control offers the best hope for sustainable management of WSS. Entomopathogenic nematodes (EPNs) have been used successfully against other above-ground insect pests, and adding adjuvants to sprays containing EPNs has been shown to improve their effectiveness. We tested the hypothesis that adding chemical adjuvants to sprays containing EPNs will increase the ability of EPNs to enter wheat stems and kill diapausing WSS larvae. This is the first study to test the ability of EPNs to infect the WSS, C. cinctus, and test EPNs combined with adjuvants against C. cinctus in both the laboratory and the field. Infection assays showed that three different species of EPNs caused 60–100% mortality to WSS larvae. Adding Penterra, Silwet L-77, Sunspray 11N, or Syl-Tac to solutions containing EPNs resulted in higher WSS mortality than solutions made with water alone. Field tests showed that sprays containing S. feltiae added to 0.1% Penterra increased WSS mortality up to 29.1%. These results indicate a novel control method for WSS, and represent a significant advancement in the biological control of this persistent insect pest. PMID:28006820

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

    PubMed

    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.

  16. Suppressant effect of procarbazine and its comparison with anti-lymphocyte serum in adjuvant-induced polyarthritis in rats

    PubMed Central

    Possanza, G. J.; Stewart, P. B.

    1970-01-01

    Procarbazine, a new immunosuppressant, was active in inhibiting the lesions of experimental arthritis in rats. In comparison with anti-lymphocyte serum it was somewhat more effective in suppressing the secondary than the primary lesion of adjuvant-induced disease. The anti-inflammatory action of procarbazine could not be correlated exactly with its immunosuppressant effect. The dosage scheme which began 21 days before immunization and which had the greater effect on the immune response, did not have any greater anti-arthritic effect than the dosage scheme started on day 0. Anti-lymphocyte serum and procarbazine both produced a fall of approximately 75% in the absolute number of circulating lymphocytes, without any significant effect on other elements in the peripheral blood. PMID:4985161

  17. Coimmunization with an optimized IL15 plasmid adjuvant enhances humoral immunity via stimulating B cells induced by genetically engineered DNA vaccines expressing consensus JEV and WNV E DIII.

    PubMed

    Ramanathan, Mathura P; Kutzler, Michele A; Kuo, Yuan-Chia; Yan, Jian; Liu, Harrison; Shah, Vidhi; Bawa, Amrit; Selling, Bernard; Sardesai, Niranjan Y; Kim, J Joseph; Weiner, David B

    2009-07-09

    The Japanese encephalitis virus (JEV) and West Nile virus (WNV) are responsible for a large proportion of viral encephalitis in humans. Currently, there is no FDA approved specific treatment for either, though there are attempts to develop vaccines against both viruses. In this study, we proposed novel genetically engineered DNA vaccines against these two neurotrophic flaviviruses. The structural domain III (DIII) of E protein from these viruses is reported to carry dominant epitopes that induce neutralizing antibodies. Therefore we created consensus sequence of DIII domain across numerous strains of JEV and WNV. Based on the consensus amino acid sequence, synthetic codon and RNA optimized DIII-expressing DNA vaccine constructs with an efficient leader sequence were synthesized for immunization studies. In addition, we also constructed a genetically engineered IL15 DNA vaccine molecular adjuvant for co-stimulating the immune response against DIII clones. Vaccine constructs were delivered into BALB/C mice intramuscularly followed by electroporation using the CELLECTRA in vivo electroporator. We have observed that the combined delivery of both WNV DIII and IL15-ECRO DNA vaccine constructs resulted in not only the highest level of antibody against DIII, but also enhanced cross reactivity with two other antigens tested. Also, coimmunization with IL15 plasmid further increased the immune response by four- to five-fold. Importantly, we have shown that IL15 coimmunization adjuvanted humoral responses against DIII antigens by elevating the level of antibody secreting B cells. Such a DNA vaccine approach may better help to control potential travel related infectious agents such as JEV.

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

    PubMed Central

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

    2016-01-01

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

  19. Anti-arthritic activity of root bark of Oroxylum indicum (L.) vent against adjuvant-induced arthritis

    PubMed Central

    Karnati, Mamatha; Chandra, Rodda H; Veeresham, Ciddi; Kishan, Bookya

    2013-01-01

    Background: Oroxylum indicum (Bignoniaceae) also known as Sonapatha is an indigenous medicinal plant widely used in Ayurvedic medicine for over thousands of years. It is an active ingredient of well-known Ayurvedic formulations such as Chyawanprash and Dasamula. Root bark of this plant has tonic and astringent properties and it is also used in rheumatism. Objective: The present investigation was carried out to evaluate the anti-arthritic activity of different extracts of root bark of Oroxylum indicum against adjuvant - induced arthritis in rats. Materials and Methods: Male Wistar rats were used in this study. Arthritis was induced by injecting 0.1 ml Freund's complete adjuvant intra-dermally into the left hind paw of the rats. The paw volume, hematological, biochemical, radiographic and histopathological aspects were evaluated. Results: The relative percentage inhibition potential of paw volume in rats treated with various extracts of Oroxylum indicum was found to be ethyl acetate extract (67.69%) >chloroform extract (64.61%) >n-butanol extract (58.46%) respectively. The hematological parameters like RBC count, hemoglobin content showed significant increase while there was a significant decrease in total WBC count and ESR in all the groups of animals pretreated with root bark extracts. The biochemical parameters such as catalase, glutathione contents showed a significant increase while the lipid peroxide and Cathepsin-D content decreased significantly only in case of ethyl acetate pretreated rats when compared to others. Conclusion: The present study suggests that the chloroform, ethyl acetate and n-butanol extracts of root bark of Oroxylum indicum exhibit anti-arthritic activity. The order of activity of extracts was found to be ethyl acetate >chloroform >n-butanol respectively. PMID:23798888

  20. Ferulic acid ethyl ester diminished Complete Freund's Adjuvant-induced incapacitation through antioxidant and anti-inflammatory activity.

    PubMed

    Cunha, Francisco Valmor Macedo; Gomes, Bruno de Sousa; Neto, Benedito de Sousa; Ferreira, Alana Rodrigues; de Sousa, Damião Pergentino; de Carvalho e Martins, Maria do Carmo; Oliveira, Francisco de Assis

    2016-01-01

    Ferulic acid ethyl ester (FAEE) is a derivate from ferulic acid which reportedly has antioxidant effect; however, its role on inflammation was unknown. In this study, we investigated the orally administered FAEE anti-inflammatory activity on experimental inflammation models and Complete Freund's Adjuvant (CFA)-induced arthritis in rats. CFA-induced arthritis has been evaluated by incapacitation model and radiographic knee joint records at different observation time. FAEE (po) reduced carrageenan-induced paw edema (p < 0.001) within the 1st to 5th hours at 50 and 100 mg/kg doses. FAEE 50 and 100 mg/kg, po inhibited leukocyte migration into air pouch model (p < 0.001), and myeloperoxidase, superoxide dismutase, and catalase activities (p < 0.001) increased total thiol concentration and decreased the TNF-α and IL-1β concentrations, NO, and thiobarbituric acid reactive species. In the CFA-induced arthritis, FAEE 50 and 100 mg/kg significantly reduced the edema and the elevation paw time, a joint disability parameter, since second hour after arthritis induction (p < 0.001). FAEE presented rat joint protective activity in radiographic records (p < 0.001). The data suggest that the FAEE exerts anti-inflammatory activity by inhibiting leukocyte migration, oxidative stress reduction, and pro-inflammatory cytokines.

  1. Epigallocatechin-3-gallate ameliorates radiation-induced acute skin damage in breast cancer patients undergoing adjuvant radiotherapy

    PubMed Central

    Zhu, Wanqi; Jia, Li; Chen, Guanxuan; Zhao, Hanxi; Sun, Xiaorong; Meng, Xiangjiao; Zhao, Xianguang; Xing, Ligang; Yu, Jinming; Zheng, Meizhu

    2016-01-01

    There are few effective treatment options for radiation-induced dermatitis in breast cancer patients. We conducted a single-arm trial to tested the hypothesis that topical epigallocatechin-3-gallate (EGCG) is effective against radiation-induced dermatitis in breast cancer patients undergoing radiotherapy. Forty-nine patients participated in this study. The patients underwent mastectomy followed by adjuvant radiotherapy. Topical EGCG was applied daily, starting when grade I dermatitis appeared and ending two weeks after radiotherapy. The maximum dermatitis observed during the EGCG treatment was as follows: Grade 1 toxicity, 71.4% (35 patients); grade 2 toxicity, 28.6% (14 patients); there were no patients with grade 3 or 4 toxicity. The majority of the radiation-induced dermatitis was observed 1 week after the end of radiotherapy. EGCG reduced the pain in 85.7% of patients, burning-feeling in 89.8%, itching in 87.8%, pulling in 71.4%, and tenderness in 79.6%. These findings suggest topical EGCG may be an effective treatment for radiation-induced dermatitis and has acceptable toxicity. PMID:27224910

  2. Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens

    PubMed Central

    Knudsen, Niels Peter H.; Olsen, Anja; Buonsanti, Cecilia; Follmann, Frank; Zhang, Yuan; Coler, Rhea N.; Fox, Christopher B.; Meinke, Andreas; D´Oro, Ugo; Casini, Daniele; Bonci, Alessandra; Billeskov, Rolf; De Gregorio, Ennio; Rappuoli, Rino; Harandi, Ali M.; Andersen, Peter; Agger, Else Marie

    2016-01-01

    The majority of vaccine candidates in clinical development are highly purified proteins and peptides relying on adjuvants to enhance and/or direct immune responses. Despite the acknowledged need for novel adjuvants, there are still very few adjuvants in licensed human vaccines. A vast number of adjuvants have been tested pre-clinically using different experimental conditions, rendering it impossible to directly compare their activity. We performed a head-to-head comparison of five different adjuvants Alum, MF59®, GLA-SE, IC31® and CAF01 in mice and combined these with antigens from M. tuberculosis, influenza, and chlamydia to test immune-profiles and efficacy in infection models using standardized protocols. Regardless of antigen, each adjuvant had a unique immunological signature suggesting that the adjuvants have potential for different disease targets. Alum increased antibody titers; MF59® induced strong antibody and IL-5 responses; GLA-SE induced antibodies and Th1; CAF01 showed a mixed Th1/Th17 profile and IC31® induced strong Th1 responses. MF59® and GLA-SE were strong inducers of influenza HI titers while CAF01, GLA-SE and IC31® enhanced protection to TB and chlamydia. Importantly, this is the first extensive attempt to categorize clinical-grade adjuvants based on their immune profiles and protective efficacy to inform a rational development of next generation vaccines for human use. PMID:26791076

  3. Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens.

    PubMed

    Knudsen, Niels Peter H; Olsen, Anja; Buonsanti, Cecilia; Follmann, Frank; Zhang, Yuan; Coler, Rhea N; Fox, Christopher B; Meinke, Andreas; D'Oro, Ugo; Casini, Daniele; Bonci, Alessandra; Billeskov, Rolf; De Gregorio, Ennio; Rappuoli, Rino; Harandi, Ali M; Andersen, Peter; Agger, Else Marie

    2016-01-21

    The majority of vaccine candidates in clinical development are highly purified proteins and peptides relying on adjuvants to enhance and/or direct immune responses. Despite the acknowledged need for novel adjuvants, there are still very few adjuvants in licensed human vaccines. A vast number of adjuvants have been tested pre-clinically using different experimental conditions, rendering it impossible to directly compare their activity. We performed a head-to-head comparison of five different adjuvants Alum, MF59®, GLA-SE, IC31® and CAF01 in mice and combined these with antigens from M. tuberculosis, influenza, and chlamydia to test immune-profiles and efficacy in infection models using standardized protocols. Regardless of antigen, each adjuvant had a unique immunological signature suggesting that the adjuvants have potential for different disease targets. Alum increased antibody titers; MF59® induced strong antibody and IL-5 responses; GLA-SE induced antibodies and Th1; CAF01 showed a mixed Th1/Th17 profile and IC31® induced strong Th1 responses. MF59® and GLA-SE were strong inducers of influenza HI titers while CAF01, GLA-SE and IC31® enhanced protection to TB and chlamydia. Importantly, this is the first extensive attempt to categorize clinical-grade adjuvants based on their immune profiles and protective efficacy to inform a rational development of next generation vaccines for human use.

  4. Successful reduction of alopecia induced by anthracycline and taxane containing adjuvant chemotherapy in breast cancer - clinical evaluation of sensor-controlled scalp cooling.

    PubMed

    Friedrichs, Kay; Carstensen, Martin H

    2014-01-01

    Scalp cooling is a long known method to reduce chemotherapy-induced alopecia in cancer patients with solid tumors. Due to a progress in this method, a medical device enabling individual feedback-controlled temperature regulation was evaluated. Between June 2011 and December 2012, 83 breast cancer patients were included. Evaluation was focussed on the quantification of alopecia, satisfaction and side effects of the scalp cooling system in (neo-) adjuvant chemotherapy regimens. Alopecia quantification was done by patient evaluation and experts rating. Based on patient hair loss evaluations, the mean overall success rate of scalp cooling (<50% hair loss) in (neo-) adjuvant chemotherapy was at 52.6%. 51.7% of patients in (neo-) adjuvant CT did not need head covers. In 51.7% of patients in (neo-) adjuvant chemotherapy hair regrowth occurred. Patient satisfaction rate was between VAS 70 and 80 (0-100, where 100 is completely satisfied). The evaluation demonstrates that feedback-controlled scalp cooling provides a good chance for breast cancer patients to keep their hair even during (neo-)adjuvant chemotherapies, which are known to cause severe to complete alopecia without scalp cooling.

  5. Protective immunity induced in Aotus monkeys by a recombinant SERA protein of Plasmodium falciparum: adjuvant effects on induction of protective immunity.

    PubMed Central

    Inselburg, J; Bathurst, I C; Kansopon, J; Barchfeld, G L; Barr, P J; Rossan, R N

    1993-01-01

    We report the results of vaccination trial 2 of Panamanian Aotus monkeys with a recombinant blood-stage antigen, SERA 1, of the malaria parasite Plasmodium falciparum. Monkeys were immunized with SERA 1, a 262-amino-acid fragment (amino acids 24 to 285) of the 989-amino-acid SERA protein produced by the Honduras 1 strain of the parasite. Immunization mixtures contained 100 micrograms of recombinant SERA 1 protein per dose mixed with one of five different adjuvants. The protein mixed with either Freund's adjuvant or MF75.2 adjuvant stimulated protective immunity. When other P. falciparum antigens were included in the SERA 1-Freund's adjuvant mixture, no protective immunity was observed, although high anti-SERA 1 antibody titers were produced. Three other adjuvants mixed with SERA 1 failed to induce a protective immune response. These results, their relationship to those reported previously in the first vaccination trial (trial 1), and their relationships to the quantitative measurement of anti-SERA 1 antibodies in enzyme-linked immunosorbent assays provided insights into the induction of a protective immune response in vaccinated monkeys. PMID:8478092

  6. Efficacy of vaccination with different combinations of MF59-adjuvanted and nonadjuvanted seasonal and pandemic influenza vaccines against pandemic H1N1 (2009) influenza virus infection in ferrets.

    PubMed

    van den Brand, Judith M A; Kreijtz, Joost H C M; Bodewes, Rogier; Stittelaar, Koert J; van Amerongen, Geert; Kuiken, Thijs; Simon, James; Fouchier, Ron A M; Del Giudice, Giuseppe; Rappuoli, Rino; Rimmelzwaan, Guus F; Osterhaus, Albert D M E

    2011-03-01

    Serum antibodies induced by seasonal influenza or seasonal influenza vaccination exhibit limited or no cross-reactivity against the 2009 pandemic swine-origin influenza virus of the H1N1 subtype (pH1N1). Ferrets immunized once or twice with MF59-adjuvanted seasonal influenza vaccine exhibited significantly reduced lung virus titers but no substantial clinical protection against pH1N1-associated disease. However, priming with MF59-adjuvanted seasonal influenza vaccine significantly increased the efficacy of a pandemic MF59-adjuvanted influenza vaccine against pH1N1 challenge. Elucidating the mechanism involved in this priming principle will contribute to our understanding of vaccine- and infection-induced correlates of protection. Furthermore, a practical consequence of these findings is that during an emerging pandemic, the implementation of a priming strategy with an available adjuvanted seasonal vaccine to precede the eventual pandemic vaccination campaign may be useful and life-saving.

  7. Efficacy of Vaccination with Different Combinations of MF59-Adjuvanted and Nonadjuvanted Seasonal and Pandemic Influenza Vaccines against Pandemic H1N1 (2009) Influenza Virus Infection in Ferrets▿

    PubMed Central

    van den Brand, Judith M. A.; Kreijtz, Joost H. C. M.; Bodewes, Rogier; Stittelaar, Koert J.; van Amerongen, Geert; Kuiken, Thijs; Simon, James; Fouchier, Ron A. M.; Del Giudice, Giuseppe; Rappuoli, Rino; Rimmelzwaan, Guus F.; Osterhaus, Albert D. M. E.

    2011-01-01

    Serum antibodies induced by seasonal influenza or seasonal influenza vaccination exhibit limited or no cross-reactivity against the 2009 pandemic swine-origin influenza virus of the H1N1 subtype (pH1N1). Ferrets immunized once or twice with MF59-adjuvanted seasonal influenza vaccine exhibited significantly reduced lung virus titers but no substantial clinical protection against pH1N1-associated disease. However, priming with MF59-adjuvanted seasonal influenza vaccine significantly increased the efficacy of a pandemic MF59-adjuvanted influenza vaccine against pH1N1 challenge. Elucidating the mechanism involved in this priming principle will contribute to our understanding of vaccine- and infection-induced correlates of protection. Furthermore, a practical consequence of these findings is that during an emerging pandemic, the implementation of a priming strategy with an available adjuvanted seasonal vaccine to precede the eventual pandemic vaccination campaign may be useful and life-saving. PMID:21209108

  8. Vaccines, adjuvants and autoimmunity.

    PubMed

    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.

  9. Recombinant human endostatin inhibits TNF-alpha-induced receptor activator of NF-κB ligand expression in fibroblast-like synoviocytes in mice with adjuvant arthritis.

    PubMed

    Gao, Qiu-Fang; Zhang, Xiu-Hong; Yuan, Feng-Lai; Zhao, Ming-Dong; Li, Xia

    2016-12-01

    Bone loss is a critical pathology responsible for the functional disability in patients with rheumatoid arthritis (RA). It is well known that receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) plays a crucial role in bone loss in RA. The purpose of this study was to determine whether recombinant human endostatin (rh-endostatin) mediates bone erosion in RA by regulation of RANKL expression in an experimental model of RA, consisting of mice with adjuvant-induced arthritis (AA). Cultured AA fibroblast-like synoviocytes (FLSs) obtained from these mice were induced by tumor necrosis factor-α (TNF-α) combined with or without rh-endostatin. The levels of RANKL and osteoprotegerin (OPG) mRNA, soluble and membrane-bound proteins were assessed by real-time PCR, ELISA, and Western blotting. Western blotting and the luciferase reporter assay were used to study related signaling pathways. Rh-endostatin inhibited RANKL mRNA expression, soluble and membrane-bound protein expression in AA FLSs but not in CD4+ T cells. However, OPG expression and secretion was not affected by rh-endostatin in AA FLSs. Molecular analysis demonstrated that rh-endostatin significantly inhibited TNF-α-induced MAPK and AP-1 signaling pathways. Moreover, rh-endostatin attenuated TNF-α-induced NF-κB signaling by suppressing the phosphorylation level of inhibitor kappaBα (IκBα) and nuclear translocation of NF-κB p65 in FLSs from mice with AA. These results provide the first evidence that rh-endostatin inhibits TNF-α-induced RANKL expression in AA FLSs.

  10. Efficacy of Scalp Cooling in Preventing Chemotherapy-Induced Alopecia in Breast Cancer Patients Receiving Adjuvant Docetaxel and Cyclophosphamide Chemotherapy.

    PubMed

    Cigler, Tessa; Isseroff, Devora; Fiederlein, Barbara; Schneider, Sarah; Chuang, Ellen; Vahdat, Linda; Moore, Anne

    2015-10-01

    Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of many chemotherapy agents. The TC (docetaxel [Taxotere] and cyclophosphamide) chemotherapy regimen is typically associated with complete alopecia. Scalp cooling with cold caps has been reported to minimize or prevent CIA. We conducted a prospective study to assess efficacy of scalp cooling in preventing CIA among women receiving adjuvant TC chemotherapy for breast cancer. Women at the Weill Cornell Breast Center who independently elected to use scalp cooling with cold caps during adjuvant TC chemotherapy were asked to participate. Degree of hair loss was assessed by a single practitioner using Dean's alopecia scale (grade 1/excellent [< 25% hair loss], grade 2/good [25%-50% hair loss], grade 3/moderate [50%-75% hair loss], grade 4/poor [> 75% hair loss]), by digital photographs, and by patient self-report of hair thinning or the need to wear a wig/head covering, or both. Assessments were made before each chemotherapy treatment and at follow-up visits between 3 weeks and 3 months after completion of chemotherapy. Of 20 evaluable patients, 10% reported a need to wear a wig/head covering at the follow-up visit. Dean's alopecia score was excellent for 65% of patients, good for 25% of patients, and moderate or poor for 10% of patients. The majority of patients reported hair thinning after every chemotherapy cycle. No patient discontinued therapy because of an intolerance to cold caps. Scalp cooling with cold caps appears to be effective in preventing CIA among the majority of women undergoing treatment with TC chemotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    SciTech Connect

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

    2014-01-05

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

  12. Carbohydrate-based immune adjuvants

    PubMed Central

    Petrovsky, Nikolai; Cooper, Peter D

    2011-01-01

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

  13. Postoperative adjuvant chemotherapy combined with intracavitary brachytherapy in early-stage cervical cancer patients with intermediate risk factors

    PubMed Central

    Yu, Hao; Zhang, Linlin; Du, Xuelian; Sheng, Xiugui

    2016-01-01

    Objective To investigate the impact of postoperative adjuvant therapy on survival of patients with intermediate risk early-stage cervical squamous cell carcinoma. Methods A total of 133 consecutive patients with intermediate risk early-stage cervical squamous cell carcinoma treated at Shandong Cancer Hospital and Institute from February 2010 to March 2014 were enrolled in our study. All patients received adjuvant therapy and were subdivided into three groups: pelvic radiotherapy (RT; N=42), adjuvant chemotherapy + intracavitary radiotherapy (CT+ICRT; N=47), or concurrent chemoradiation (CCRT; N=44). Disease-free survival (DFS) and therapeutic complications were evaluated. Results There were no significant differences in DFS for patients treated with RT, CT+ICRT, and CCRT (P>0.05) with 3-year rates of 94.0%, 93.4%, and 97.6%, respectively. Frequencies of grade III–IV acute toxicities were higher in patients treated with CCRT (34.1%) than those treated with RT (9.5%) or CT+ICRT (16.7%; P<0.05), with no significant differences observed between RT and CT+ICRT groups (P>0.05). Grade I–II late toxicities were higher in CCRT (25%), followed by RT (19.0%), and finally, the CT+ICRT group (4.3%; P<0.05); with no significant differences observed between CCRT and RT groups (P>0.05). Conclusion Treatment with CT+ICRT or RT resulted in the equivalent of 3-year DFS compared to CCRT, but fewer therapeutic complications were observed with CT for patients with intermediate risk early-stage cervical squamous cell carcinoma. PMID:27942225

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

    PubMed

    Chen, Lijuan; Bao, Bin; Wang, Nanping; Xie, Jing; Wu, Wenhui

    2012-03-28

    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). 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. 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. 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 administration of SCII might be a potential candidate as a novel drug for further

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

    PubMed Central

    Chen, Lijuan; Bao, Bin; Wang, Nanping; Xie, Jing; Wu, Wenhui

    2012-01-01

    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. Protective effect of Withania somnifera root powder in relation to lipid peroxidation, antioxidant status, glycoproteins and bone collagen on adjuvant-induced arthritis in rats.

    PubMed

    Rasool, M; Varalakshmi, P

    2007-04-01

    The present investigation was carried out to evaluate the protective effect of Withania somnifera Linn. Dunal (family-Solanaceae), commonly known as Ashwagandha, on adjuvant-induced arthritic rats. Results were compared with those for Indomethacin, a nonsteroidal anti-inflammatory drug. Arthritis was induced by intradermal 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. The anti-arthritic effect of W. somnifera root powder was assessed by measuring changes in lipid peroxidation, antioxidant status, and glycoprotein levels in plasma and spleen of arthritic animals. In addition, cartilage degradation was also assessed by estimating bone collagen, and urinary constituents in arthritic animals. Results of the present investigation showed significant increase in the level of lipid peroxides, glycoproteins, and urinary constituents with the depletion of antioxidant status and bone collagen in arthritic animals. These biochemical alterations observed were ameliorated significantly by oral administration of W. somnifera root powder (1000 mg/kg body weight) in arthritic animals. The results of this study clearly indicate that W. somnifera root powder is capable of rectifying the above biochemical changes in adjuvant arthritis.

  17. The effects of CpG-ODNs and Chitosan adjuvants on the elicitation of immune responses induced by the HIV-1-Tat-based candidate vaccines in mice.

    PubMed

    Alipour, Samira; Mahdavi, Atiyeh; Abdoli, Asghar

    2017-03-01

    HIV1-Tat-based vaccines could elicit broad, durable and neutralizing immune responses and are considered as potential AIDS vaccines. The present study aims to formulate CpG-ODNs adjuvant and Chitosan with Tat protein to enhance the immunogenicity of HIV-1-Tat-based candidate vaccines and to investigate their efficacies in mice. To this end, we added CpG-ODNs, Chitosan and Alum as adjuvants to the Tat-based candidate vaccine formulations. Then, we compared frequency and magnitude of both humoral and cellular immune responses from mice immunized with the adjuvant-formulated Tat candidate vaccines against those obtained from mice immunized with recombinant Tat protein alone. Mice were subcutaneously immunized three times at 2-week intervals with the candidate vaccines. Measurements of anti-Tat immune responses showed that all vaccinated groups had a good immunity compared to the control groups and developed high levels of both humoral and cellular responses. However, immunized mice with CpG-ODNs, and Chitosan-adjuvanted Tat vaccines elicited stronger T-cell responses (both humoral and cellular immunity) compared to the others. These data suggest that co-administration of recombinant Tat protein with CpG-ODNs and Chitosan may serve as a potential formulation for enhancing of the Tat vaccine-induced immunity and might have effects on shaping Th polarization induced by HIV1-Tat protein vaccines. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

    PubMed

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

    1997-01-01

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

  19. The PorB porin from commensal Neisseria lactamica induces Th1 and Th2 immune responses to ovalbumin in mice and is a potential immune adjuvant.

    PubMed

    Liu, Xiuping; Wetzler, Lee M; Massari, Paola

    2008-02-06

    Porins from pathogenic Neisseriae are among several bacterial products with immune adjuvant activity. Neisseria meningitidis (Nme) PorB, has been shown to induce immune cells activation in a TLR2-dependent manner and acts as a vaccine immune adjuvant. The PorB porin from Neisseria lactamica (Nlac), a common nasopharyngeal commensal, shares significant structural and functional similarities with Nme PorB. In this work we ask whether the immune adjuvant ability of porins from pathogenic Neisserial strains is a characteristic shared with porins from non-pathogenic Neisserial species or whether it is unique for bacterial products derived from microorganisms capable of inducing inflammation and disease. We evaluated the potential immune adjuvant effect of Nlac PorB in mice using ovalbumin (OVA) as a prototype antigen. Immunization with Nlac PorB/OVA induced high OVA-specific IgG and IgM titers compared to OVA alone, similar to other adjuvants such as Nme PorB and alum. High titers of IgG1 and IgG2b were detected as well as production of IL-4, IL-10, IL-12 and INF-gamma in response to Nlac PorB, consistent with induction of both a Th1-type and a Th2-type immune response. OVA-specific proliferation was also determined in splenocytes from Nlac PorB/OVA-immunized mice. In addition, B cell activation in vitro and cytokine production in response to Nlac PorB was found to be mediated by TLR2, in a similar manner to Nme PorB.

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

    PubMed

    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.

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

    PubMed Central

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

    2016-01-01

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

  2. The Impact of Synovial NF-κB Activation on Apoptosis Pattern Change During Adjuvant-induced Inflammation

    PubMed Central

    Golabi, Sahar; Zaringhalam, Jalal; Manaheji, Homa

    2017-01-01

    Introduction: Apoptosis dysregulation plays a substantial role in the pathophysiology of chronic inflammation and its related symptoms such as edema. Regulation of NF-κB activation is involved in apoptosis pattern change. The current study aimed at verifying the effects of local inflammation on edema and changes in apoptotic markers, and investigating the possible role of NF-κB in apoptosis pattern change during different stages of complete Freund’s adjuvant (CFA)-induced knee arthritis in rats. Methods: A total of 96 male Wistar rats were divided into different experimental groups. Arthritis was evoked into the right knee articular joint. Changes made in knee edema were assessed by caliper on the days 0, 7, 14, and 21 of the study. Synovial NF-κB and levels of apoptotic markers were evaluated during different stages of the study using Western blot technique. Results: CFA injection caused intense edema during the whole study period. Synovial NF-κB level increased during the whole study period. The level of apoptotic markers increased during the acute phase of study. But during chronic phase, the apoptosis level decreased. Inh-NF-κB administration increased synovial apoptosis during the whole study period. 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-κB had a crucial role in synovial apoptosis change during the study period. PMID:28781725

  3. Cardiac safety of adjuvant non-pegylated liposomal doxorubicin combined with cyclophosphamide and followed by paclitaxel in older breast cancer patients.

    PubMed

    Coltelli, Luigi; Fontana, Andrea; Lucchesi, Sara; Ginocchi, Laura; Bocci, Guido; Filidei, Mario; Scalese, Marco; Arrighi, Giada; Finale, Chiara; Marcucci, Lorenzo; Goletti, Orlando; Salvadori, Barbara; Ferrarini, Ilaria; Bona, Eleonora; Falcone, Alfredo; Allegrini, Giacomo

    2017-02-01

    To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) combined to Cyclophosphamide (CTX) and followed by weekly Paclitaxel, in older patients (≥65 years) with diagnosis of high risk breast cancer. The main end point of this prospective study was the detection of early episodes of symptomatic congestive heart failure (CHF). The cardiac function was evaluated by left ventricular ejection fraction (LVEF) measurements with repeated echocardiograms, performed 2 weeks before the beginning of chemotherapy and every 6 months, until 30 months after the study entry; then yearly for at least 5 years. Forty-seven patients were enrolled from two Italian Divisions of Medical Oncology. Final results revealed no early episodes of symptomatic CHF within the first 12 months from the enrolment. Only two cardiac events were observed: an episode of atrial flutter after the first cycle of NPL-DOX and CTX, with a quick return to normal rhythm, and a grade 3 (scored to NCI-CTCAE, version 3.0) CHF episode, 18 months later chemotherapy start. No other relevant toxicities were reported. This adjuvant combination including NPL-DOX in elderly patients, resulted in a low rate of cardiac toxic effects. Comparative trials should be encouraged to confirm these findings. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Amelioration of FCA induced arthritis on topical application of curcumin in combination with emu oil.

    PubMed

    Jeengar, Manish Kumar; Shrivastava, Shweta; Mouli Veeravalli, S Chandra; Naidu, V G M; Sistla, Ramakrishna

    2016-09-01

    The aim of the present study was to investigate the skin penetration potential of emu oil and the possibility of enhancing the antiarthritic potential of lipophilic bioactive curcumin, which has poor permeability through biological membranes. Solubility and ex vivo skin permeation studies were performed with water, corn oil, and emu oil as a vehicle using curcumin as a model drug. Carrageenan induced inflammation and Freund's complete adjuvant-induced arthritic rat models were used to evaluate enhanced antiinflammatory and antiarthritic effect of curcumin in combination of emu oil via topical route. The skin permeation study resulted in the combination of emu oil with curcumin enhancing the flux 1.84 and 4.25 times through the rat skin compared to corn oil and water, respectively. Results of carrageenan induced rat paw edema model demonstrated that percentage of paw inhibition shown by curcumin-emu oil combination was 1.42-fold more compared to the total effect shown by both groups treated with curcumin aqueous suspension and emu oil per se. In Freund's complete adjuvant-induced arthritic model, the combined treatment was effective in bringing significant changes in the functional, biochemical, histopathologic, and radiologic parameters. Topical application of curcumin-emu oil combination resulted in significant reduced levels of proinflammatory mediators TNF-α, IL-1 β, and IL-6 (P < 0.05, 0.001, and 0.01, respectively) compared to arthritic animals. Topical delivery of curcumin with emu oil holds promise as a noninvasive and efficacious intervention for the treatment of inflammatory arthritis and it assists in further development of a topical formulation of curcumin using emu oil as a vehicle. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Synergistic protection against acute flurothyl-induced seizures by adjuvant treatment of the ketogenic diet with the type 2 diabetes drug pioglitazone.

    PubMed

    Simeone, Timothy A; Matthews, Stephanie A; Simeone, Kristina A

    2017-08-01

    We have previously found that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) contributes to the mechanism of action of the ketogenic diet (KD), an established treatment for pediatric refractory epilepsy. We have found that the KD increases brain PPARγ and that inhibition or genetic loss of PPARγ prevents the antiseizure effects of the KD on (1) acutely induced seizures in nonepileptic mice and (2) spontaneous recurrent seizures in epileptic mice. Here, we tested the hypothesis that adjuvant treatment of KD-treated mice with a PPARγ agonist, pioglitazone, would result in an additive effect. Acute seizures were induced in three groups of C57Bl/6 mice by inhalation exposure to flurothyl gas. In Group 1, mice were weaned onto either a standard diet or KD comprised of a fat:carbohydrate/protein ratio of either 6:1, 3:1, or 1:1 for 2 weeks. In Group 2, vehicle or pioglitazone (0.1, 1, 10, 80 mg/kg) was administered 4 h prior to flurothyl exposure. In Group 3, vehicle or increasing doses of pioglitazone were administered to KD-treated mice 4 h prior to flurothyl exposure. Latency times to clonic seizures and generalized tonic-clonic (GTC) seizures were recorded, and isobolographic analysis was used to determine combinatorial interactions. Neither KD treatment nor pioglitazone alone or in combination affected clonic seizures. However, the latency to GTC seizures was dose-dependently and significantly increased by both KD (~57%, p < 0.05) and pioglitazone (~28%, p < 0.05). Coadministration of an ineffective 1:1 KD and pioglitazone resulted in ~47-55% (p < 0.05) increase in latency to GTC. Isobolographic analysis indicated a synergistic interaction of the KD and pioglitazone. These results suggest coadministration may enable reduction of the KD ratio without loss of seizure protection. Such adjuvant treatment could improve quality of life and limit adverse effects of a classic KD or high-dose pioglitazone. Wiley Periodicals, Inc

  6. Application of outer membrane vesicle of Neisseria meningitidis serogroup B as a new adjuvant to induce strongly Th1-oriented responses against HIV-1.

    PubMed

    Aghasadeghi, Mohammad Reza; Salmani, Ali Sharifat; Sadat, Seyed Mehdi; Javadi, Foozieh; Memarnejadian, Arash; Vahabpour, Rouhoullah; Zabihollahi, Rezvan; Moshiri, Arfa; Siadat, Seyed Davar

    2011-12-01

    Despite the worldwide efforts made in the field of HIV vaccine development, an efficient AIDS vaccine strategy is still vague. Virus-like particles (VLPs) are one of the introduced aspects for HIV vaccine development since the non-replicative nature of HIV VLPs, resulting from the lack of viral genomic RNA, makes them suitable for broad applications. We have previously designed and introduced non-infectious VLPs (mzNL4-3) by introduction of a deletion mutation in the reverse transcriptase and integrase coding regions of HV-1. There are evidences suggesting that an effective cellular immune response against HIV-1 is able to control and suppress viremia during primary and chronic HIV infections. In the present study we have evaluated the potency of mzNL4-3 VLPs mixed with Neisseria meningitidis serogroup B outer-membrane vesicle (OMV), which is among the microbial components with proved adjuvant properties, to induce humoral and cellular responses against HIV-1. Analysis of anti-HIV-1 responses elicited in immunized BALB/c mice following different immunization regimens indicated OMV+VLP as an immunopotent combination which significantly induced anti-HIV-1 IgG with IgG2a dominancy. Results of cytokine and ELISpot assays also showed the capability of VLP+OMV immunogen for effective induction of IFN-gamma; and IL4 secreting cells and further suggested the promotion of Th1-oriented response that was evidenced with the increased IFN-γ/IL4 secretion ratio. According to our study, HIV-1 VLPs combined with N. meningitidis B OMVs seem to be a promising approach in vaccine development against HIV-1.

  7. Gene-inducing program of human dendritic cells in response to BCG cell-wall skeleton (CWS), which reflects adjuvancy required for tumor immunotherapy.

    PubMed

    Ishii, Kazuo; Kurita-Taniguchi, Mitsue; Aoki, Mikio; Kimura, Toru; Kashiwazaki, Yasuo; Matsumoto, Misako; Seya, Tsukasa

    2005-05-15

    Adjuvants induce the expression of a number of genes in dendritic cells (DCs), which facilitate effective antigen-presentation and cytokine/chemokine liberation. It has been accepted that the toll-like receptor (TLR) family governs the adjuvant activity in DCs. An adjuvant with a long history is mycobacteria in an oil-in-water emulsion, namely Freund's complete adjuvant. Since the active center for the adjuvancy in mycobacteria is the cell-wall skeleton (CWS), we used the bacillus Calmette-Guerin cell-wall skeleton (BCG-CWS) to test DC maturation by GeneChip analysis. We identified the genes supporting an efficient DC response and output. Approximately 2000 genes were up-regulated by BCG-CWS stimulation. BCG-CWS-, peptidoglycan (PGN)- and lipopolysaccharide (LPS)-stimulation generally up-regulated some gene clusters including genes for inflammatory cytokines (TNF, IL1alpha, IL1beta, IL6, IL12 p40, IL23 p19, etc.), chemokines (CCL20, IL8, etc.), cell adhesion molecules (ICAM-1, etc.), apoptosis-related proteins (GADD45B, BCL2A1, etc.), metabolic enzymes (PTGS2, SOD2, etc.) and miscellaneous proteins (EHD1, TNFAIP6, etc.). LPS-stimulation, but not BCG-CWS- or PGN-stimulation, up-regulated the interferon-inducible antiviral proteins, including IFIT1, IFIT2, IFIT4, CXCL10, ISG15, OASL, IFITM1 and MX1. We also found that the BCG-CWS- or PGN-stimulation up-regulated CXCL5, MMP1, etc. We discussed their properties in association with TLRs and recently discovered TLR adapters.

  8. Anti-arthritic effects of Ephedra sinica STAPF herb-acupuncture: inhibition of lipopolysaccharide-induced inflammation and adjuvant-induced polyarthritis.

    PubMed

    Yeom, Mi-Jung; Lee, Han-Chang; Kim, Gun-Ho; Lee, Hye-Jung; Shim, Insop; Oh, Seung-Kyu; Kang, Sung-Keel; Hahm, Dae-Hyun

    2006-01-01

    Anti-inflammatory and anti-arthritic effects of water distillates of Ephedra sinica STAPF (ES), in herb-acupuncture, on the inflammatory responses of arthritis was investigated using phorbol 12-myristate 13-acetate (PMA)/lipopolysaccharide (LPS)-induced human macrophage and adjuvant-induced arthritic rat. The luciferase reporter vectors driven by the tumor necrosis factor (TNF)-alpha and cyclooxygenase-2 promoters were transiently transfected into U937 cells, which were then differentiated and stimulated by PMA and LPS, respectively, to develop an in vitro anti-inflammation assay system. The luciferase activities, observed in the activated U937 cells, were significantly inhibited by ES herb-acupuncture, compared to those of PD98509 and berberine. To evaluate ES herb-acupuncture as a novel anti-arthritic therapy, a polyarthritic rat model was developed using heat-killed Mycobacterium tuberculosis, and 50 mul of ES distillate was subcutaneously injected into the ST36 acupoint on each knee joint. While the articular indexes of arthritic rats were evidently decreased by ES herb-acupuncture, their body weights did not regain their initial levels. This may be due to the accelerating effects of ES on weight-loss and fat consumption. The mRNA expressions of TNF-alpha and interleukin (IL)-6 genes, which were closely stimulated in the arthritic rat joints, were found to be restored to the normal levels through the ES treatment. In the case of IL-1beta, the recovery was not significant but substantial. The anti-arthritic effect of ES herb-acupuncture was not found in the ES-treated/non-acupoint group. In conclusion, the ES herb-acupuncture into the ST36 acupoint was found to be effective in alleviating the inflammatory response and thus arthritic symptoms in adjuvant-induced arthritic rats.

  9. Co-administration of water containing magnesium ion prevents loxoprofen-induced lesions in gastric mucosa of adjuvant-induced arthritis rat.

    PubMed

    Nagai, Noriaki; Takeda, Atsushi; Itanami, Yuri; Ito, Yoshimasa

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) comprise one of the most frequently used classes of medicines in the world; however, NSAIDs have significant side effects, such as gastroenteropathy, and rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAID-induced gastric lesions as compared to patients with other diseases. In Asian countries, loxoprofen has been used clinically for many years as a standard NSAID. We demonstrate the preventive effect of the co-administration of water containing magnesium ion (magnesium water, 1-200 µg/kg) on the ulcerogenic response to loxoprofen in adjuvant-induced arthritis (AA) rats. Oral administration of loxoprofen (100 mg/kg) caused hemorrhagic lesions in the gastric mucosa of AA rats 14 d after adjuvant injection, and, following loxoprofen administration, the lesion score of AA rats was significantly higher than that of normal rats. The expression of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in the gastric mucosa of AA rats were also increased by the administration of loxoprofen, and the increase in lesions and NO were prevented by the administration of aminoguanidine, an iNOS inhibitor. The co-administration of magnesium water decreased the ulcerogenic response to loxoprofen in AA rats. In addition, the co-administration of magnesium water attenuated the increase in iNOS mRNA expression and NO production in AA rats receiving loxoprofen. These results suggest that the oral co-administration of magnesium water to AA rats has a potent preventive effect on the ulcerogenic response to loxoprofen, probably by inhibiting the rise in iNOS and NO levels in the gastric mucosa.

  10. Nasal Vaccination with the 40-Kilodalton Outer Membrane Protein of Porphyromonas gingivalis and a Nontoxic Chimeric Enterotoxin Adjuvant Induces Long-Term Protective Immunity with Reduced Levels of Immunoglobulin E Antibodies▿

    PubMed Central

    Momoi, Fumiki; Hashizume, Tomomi; Kurita-Ochiai, Tomoko; Yuki, Yoshikazu; Kiyono, Hiroshi; Yamamoto, Masafumi

    2008-01-01

    In this study, we demonstrated that the 40-kDa outer membrane protein of Porphyromonas gingivalis (40-kDa OMP) nasally administered with a nontoxic chimeric adjuvant that combines the A subunit of mutant cholera toxin E112K with the pentameric B subunit of heat-labile enterotoxin from enterotoxigenic Escherichia coli (mCTA/LTB) elicited a long-term protective immune response. Immunization with the 40-kDa OMP and mCTA/LTB induced high levels of 40-kDa-OMP-specific immunoglobulin G (IgG) and IgA antibodies (Abs) in sera and elicited a significant IgA anti-40-kDa OMP Ab response in saliva. These Ab responses were maintained for at least 1 year after the immunization. Although using adjuvant mCTA/LTB gave Ab responses in the saliva comparable to those obtained using native cholera toxin (nCT) as the adjuvant, the levels of total IgE and 40-kDa-OMP-specific IgE Abs as well as interleukin-4 levels induced by the immunization with mCTA/LTB were lower than those induced by the immunization with nCT. Importantly, IgG Abs generated by nasal immunization with the 40-kDa OMP plus mCTA/LTB inhibited the coaggregation and hemagglutinin activities of P. gingivalis. Furthermore, the mice given nasal 40-kDa OMP plus mCTA/LTB showed a significant reduction of alveolar bone loss caused by oral infection with P. gingivalis even 1 year after the immunization compared to the loss in unimmunized mice. Because mCTA/LTB is nontoxic, nasally administered 40-kDa OMP together with mCTA/LTB should be an effective and safe mucosal vaccine against P. gingivalis infection in humans and may be an important tool for the prevention of chronic periodontitis. PMID:18411288

  11. Neurochemical sensitization associated with systemic administration of tumor necrosis factor-alpha: adjuvant action in combination with bovine serum albumin.

    PubMed

    Anisman, Hymie; Turrin, Nicolas P; Merali, Zul; Hayley, Shawn

    2003-12-01

    Tumor necrosis factor-alpha (TNF-alpha) provokes a time-dependent sensitization of brain monoamine activity, plasma corticosterone activity and sickness behavior, the latter being reminiscent of septic or anaphylactic shock. In this investigation, bovine serum albumin (BSA) elicited similar corticosterone and sickness profiles, whereas the monoamine changes were not observed. The sensitization elicited by mTNF-alpha plus BSA was markedly greater than that elicited by BSA alone. Carrier-free TNF-alpha promoted the sensitization of brain monoamine activity, but not sickness or corticosterone. It is suggested that mTNF-alpha acts as an adjuvant to the anaphylactic actions elicited by BSA, but may provoke a sensitization of monoamine activity which is time-dependent and varies across brain regions.

  12. Achillea santolina reduces serum interleukin-6 level and hyperalgesia during complete Freund's adjuvant-induced inflammation in male Wistar rats.

    PubMed

    Zaringhalam, Jalal; Akbari, Akhtar; Tekieh, Elaheh; Manaheji, Homa; Rezazadeh, Shamsali

    2010-12-01

    Immune system is involved in the etiology and pathophysiologic mechanisms of inflammation. Medicinal plants are an important source of substances which are claimed to induce non-specific immunomodulatory effects. In view of this and on account of the interleukin (IL)-6's role in inflammation and pain induction, this study investigated the effects of Achillea santolina extracts on inflammation which was induced by complete Freund's adjuvant (CFA) in male Wistar rats. Both methanolic and defatted extracts prepared from aerial parts of the plant were examined. Inflammatory symptoms such as hyperalgesia and paw edema in CFA-injected rats' paw were measured by radiant heat and plethysmometer during different stages of study respectively. Serum IL-6 level was checked by rat standard enzyme-linked immunosorbent assay specific kit. The results indicated dose-related effects of methanolic extract on paw edema, hyperalgesia and serum IL-6 level reduction in rats. Methanolic extract of A. santolina exhibited significant antihyperalgesic and anti-inflammatory effects during pretreatment and short-term treatment at dose of 200 mg/kg and there was no significant difference between 200 and 400 mg/kg doses of this extract. Defatted extract did not show significant effect on CFA-induced inflammation during different stages of treatment (P>0.05). Short-term treatment with methanolic extract at dose of 200 mg/kg was more effective than indomethacin in edema, hyperalgesia and serum IL-6 level reduction (P<0.01, P<0.01 and P<0.05 respectively). These results suggest that methanolic extract of A. santolina possesses potent anti-inflammatory and immunomodulatory activities during pretreatment and short-term administration.

  13. Safety, Correlative Markers, and Clinical Results of Adjuvant Nivolumab in Combination with Vaccine in Resected High-Risk Metastatic Melanoma

    PubMed Central

    Gibney, Geoffrey T.; Kudchadkar, Ragini R.; DeConti, Ronald C.; Thebeau, Melissa S.; Czupryn, Maria P.; Tetteh, Leticia; Eysmans, Cabell; Richards, Allison; Schell, Michael J.; Fisher, Kate J.; Horak, Christine E.; Inzunza, H. David; Yu, Bin; Martinez, Alberto J.; Younos, Ibrahim; Weber, Jeffrey S.

    2015-01-01

    Purpose The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. Experimental Design HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Results Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4+/CD4+, CD25+Treg/CD4+, and tetramer specific CD8+ T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25+Treg/CD4+ populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Conclusions Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. PMID:25524312

  14. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma.

    PubMed

    Gibney, Geoffrey T; Kudchadkar, Ragini R; DeConti, Ronald C; Thebeau, Melissa S; Czupryn, Maria P; Tetteh, Leticia; Eysmans, Cabell; Richards, Allison; Schell, Michael J; Fisher, Kate J; Horak, Christine E; Inzunza, H David; Yu, Bin; Martinez, Alberto J; Younos, Ibrahim; Weber, Jeffrey S

    2015-02-15

    The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4(+)/CD4(+), CD25(+)Treg/CD4(+), and tetramer specific CD8(+) T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25(+)Treg/CD4(+) populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. ©2014 American Association for Cancer Research.

  15. PEG modified liposomes containing CRX-601 adjuvant in combination with methylglycol chitosan enhance the murine sublingual immune response to influenza vaccination.

    PubMed

    Oberoi, Hardeep S; Yorgensen, Yvonne M; Morasse, Audrey; Evans, Jay T; Burkhart, David J

    2016-02-10

    The mucosa is the primary point of entry for pathogens making it an important vaccination site to produce a protective mucosal immune response. While the sublingual (SL) mucosa presents several barriers to vaccine penetration, its unique anatomy and physiology makes it one of the best options for mucosal vaccination. Efficient and directed delivery of adjuvants and antigens to appropriate immune mediators in the SL tissue will aid in development of effective SL vaccines against infectious diseases. Herein we demonstrate a robust immune response against influenza antigens co-delivered sublingually with engineered liposomes carrying the synthetic Toll-like receptor-4 agonist, CRX-601. Liposome modification with PEG copolymers (Pluronics), phospholipid-PEG conjugates and chitosan were evaluated for their ability to generate an immune response in a SL murine influenza vaccine model. Phospholipid-PEG conjugates were more effective than Pluronic copolymers in generating stable, surface neutral liposomes. SL vaccination with surface modified liposomes carrying CRX-601 adjuvant generated significant improvements in flu-specific responses compared with unmodified liposomes. Furthermore, the coating of modified liposomes with methylglycol chitosan produced the most effective flu-specific immune response. These results demonstrate efficient SL vaccine delivery utilizing a combination of a muco-adhesive and surface neutral liposomes to achieve a robust mucosal and systemic immune response.

  16. Scopolin isolated from Erycibe obtusifolia Benth stems suppresses adjuvant-induced rat arthritis by inhibiting inflammation and angiogenesis.

    PubMed

    Pan, Rong; Dai, Yue; Gao, Xinghua; Xia, Yufeng

    2009-07-01

    Despite scopolin is a main coumarin constituent in the stems of Erycibe obtusifolia Benth, a herb drug that has long been utilized in traditional Chinese medicine for the treatment of rheumatoid arthritis, little information is available about the pharmacological activities of this compound. The present study was performed to investigate the anti-rheumatic effects of scopolin in adjuvant-induced arthritis (AIA) in rats, and explore the underlying mechanisms of action in views of anti-inflammatory and anti-angiogenic properties in the synovial tissues. Scopolin (50, 100 mg/kg), injected intraperitoneally for 10 days from the onset of secondary response, significantly inhibited both inoculated and non-inoculated paw swelling as well as articular index scores in AIA. Meanwhile, the mean body weight of rats treated with scopolin was higher than that of model group. Rats treated with high dose of scopolin (100 mg/kg) preserved a nearly normal histological architecture of the joints and showed a significant reduction of the new blood vessels in the synovial tissues. Additionally, scopolin could reduce IL-6, VEGF and FGF-2 expressions in rat synovial tissues. In conclusion, scopolin can reduce the clinical symptoms of rat AIA by inhibiting inflammation and angiogenesis, and this compound may be a potent agent for angiogenesis related diseases and can serve as a structural base for screening more potent synthetic analogs.

  17. Highly water-soluble matrix metalloproteinases inhibitors and their effects in a rat adjuvant-induced arthritis model.

    PubMed

    Fujisawa, Tetsunori; Igeta, Katsuhiro; Odake, Shinjiro; Morita, Yasuo; Yasuda, Junko; Morikawa, Tadanori

    2002-08-01

    A new series of succinate-based dual inhibitors against matrix metalloproteinases (MMPs) and tumor necrosis factor alpha converting enzyme (TACE) possessing highly-water solubility was designed, synthesized, and evaluated for enzyme inhibition. Incorporating of acidic or basic functional groups at the P(2)' position afforded sufficient water solubility without significant loss of inhibitory potencies. Compound 18e, which had a guanidino group at the P(2)' position as the basic functional group, exhibited broad inhibition against target enzymes for a relatively long period in rat plasma (beta t(1/2); 2.0h) after sc administration when compared with compounds possessing acidic functional groups (18a and 18b). Consequently, the representative compound 18e together with compound 18b, Marimastat and Trocade were evaluated in the rat adjuvant-induced arthritis model, a model of chronic cartilage destruction. It is concluded that the newly synthesized highly water-soluble compound 18e showed significant activity in suppressing hindpaw swelling and the bone destruction with a minimal administration period (days 3-7).

  18. Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis

    PubMed Central

    Kauss, Tina; Moynet, Daniel; Rambert, Jérôme; Al-Kharrat, Abir; Brajot, Stephane; Thiolat, Denis; Ennemany, Rachid; Fawaz, Fawaz; Mossalayi, M Djavad

    2008-01-01

    Background Dietary flavonols may play an important role in the adjunct therapy of chronic inflammation. The availability of therapeutic formulations of pentahydroxyflavone glycoside, rutoside (RU), led us to investigate the ability of this molecule to modulate the release of various proinflammatory mediators from human activated macrophages in vitro and to ameliorate arthritic markers in a rat model. Methods RU was added simultaneously to human macrophages during their activation. Cells were then analyzed for inflammation-related gene expression using a specific array, and cell supernatants were collected to measure inflammatory mediators. RU was also injected into adjuvant-induced arthritic rats, and disease progression and body weight were evaluated until 50 days after injection. Sera and peritoneal macrophages were also collected to quantify the RU effect on various inflammatory markers. Results RU inhibited inflammation-related gene expression in activated human macrophages and the release of nitric oxide, tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 from these cells. In a rat model, RU inhibited clinical signs of chronic arthritis, correlating with decreased levels of inflammatory cytokines detected in rat sera and macrophage supernatants. Conclusion Thus, RU may have clinical value in reducing inflammatory manifestations in human arthritis and other inflammatory diseases. PMID:18252009

  19. Calotropis procera Latex Extract Affords Protection against Inflammation and Oxidative Stress in Freund's Complete Adjuvant-Induced Monoarthritis in Rats

    PubMed Central

    Kumar, Vijay L.; Roy, Sanjeev

    2007-01-01

    In view of the well-established anti-inflammatory properties of latex of Calotropis procera (DL), the present study was carried out to evaluate the protective effect of its methanol extract (MeDL) against inflammation and oxidative stress in monoarthritis induced by Freund's complete adjuvant (FCA) in rats. Intra-articular injection of FCA produced inflammation of the joint with a peak effect occurring on day 4 where a maximum increase in the levels of myeloperoxidase and inflammatory mediators like PGE2, TNF-α, and nitric oxide was observed. This was associated with oxidative stress with a marked reduction in the levels of glutathione, catalase, superoxide dismutase and glutathione peroxidase and an increase in the lipid peroxidation as indicated by the higher levels of thiobarbituric acid reactive substances (TBARSs). Subsequently on day 28 the histological analysis of the joint also revealed arthritic changes. Daily treatment of rats with MeDL (50 and 500 mg/kg) and standard anti-inflammatory drug rofecoxib (20 and 100 mg/kg), produced a significant attenuation in the inflammatory response and ameliorated the arthritic changes in the joint. The protection afforded by MeDL and rofecoxib was more pronounced than that of phenylbutazone and was associated with normalization of the levels of inflammatory mediators and biochemical parameters of oxidative stress. However, the overall protection afforded by rofecoxib was better than that of MeDL. PMID:17497032

  20. Calotropis procera latex extract affords protection against inflammation and oxidative stress in Freund's complete adjuvant-induced monoarthritis in rats.

    PubMed

    Kumar, Vijay L; Roy, Sanjeev

    2007-01-01

    In view of the well-established anti-inflammatory properties of latex of Calotropis procera (DL), the present study was carried out to evaluate the protective effect of its methanol extract (MeDL) against inflammation and oxidative stress in monoarthritis induced by Freund's complete adjuvant (FCA) in rats. Intra-articular injection of FCA produced inflammation of the joint with a peak effect occurring on day 4 where a maximum increase in the levels of myeloperoxidase and inflammatory mediators like PGE2, TNF-alpha, and nitric oxide was observed. This was associated with oxidative stress with a marked reduction in the levels of glutathione, catalase, superoxide dismutase and glutathione peroxidase and an increase in the lipid peroxidation as indicated by the higher levels of thiobarbituric acid reactive substances (TBARSs). Subsequently on day 28 the histological analysis of the joint also revealed arthritic changes. Daily treatment of rats with MeDL (50 and 500 mg/kg) and standard anti-inflammatory drug rofecoxib (20 and 100 mg/kg), produced a significant attenuation in the inflammatory response and ameliorated the arthritic changes in the joint. The protection afforded by MeDL and rofecoxib was more pronounced than that of phenylbutazone and was associated with normalization of the levels of inflammatory mediators and biochemical parameters of oxidative stress. However, the overall protection afforded by rofecoxib was better than that of MeDL.

  1. Self-adjuvanted nanovaccine for cancer immunotherapy: Role of lysosomal rupture-induced ROS in MHC class I antigen presentation.

    PubMed

    Wang, Ce; Li, Ping; Liu, Lanlan; Pan, Hong; Li, Hongchang; Cai, Lintao; Ma, Yifan

    2016-02-01

    MHC class I (MHC I) antigen presentation of exogenous antigens (so called "cross presentation") is a central mechanism of CD8(+) cytotoxic T lymphocyte (CTL) responses essential for successful vaccine-based cancer immunotherapy. The present study constructed amphiphilic pH-sensitive galactosyl dextran-retinal (GDR) nanogels for cancer vaccine delivery, in which dextran was conjugated with all-trans retinal (a metabolite of vitamin A) through a pH-sensitive hydrazone bond, followed by galactosylation to acquire dendritic cell (DC)-targeting ability. Our results showed that pH-sensitive GDR nanogel was a self-adjuvanted vaccine carrier that not only promoted DC maturation through activating retinoic acid receptor (RAR) signaling, but also facilitated antigen uptake and cytosolic antigen release in DCs. Furthermore, pH-sensitive GDR nanogel effectively augmented MHC I antigen presentation and evoked potent anti-cancer immune responses in vivo. More importantly, we first reported that nanoparticle-triggered lysosome rupture could directly induce ROS production in DCs, which was found to be essential for augmenting proteasome activity and downstream MHC I antigen presentation. Hence, DC-targeted pH-sensitive GDR nanogels could be a potent delivery system for cancer vaccine development. Triggering lyososomal rupture in DCs with pH-sensitive nanoparticles might be a plausible strategy to elevate intracellular ROS production for promoting antigen cross presentation, thereby improving cancer vaccine efficacy.

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

    PubMed Central

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

    2016-01-01

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

  3. The sick building syndrome as a part of the autoimmune (auto-inflammatory) syndrome induced by adjuvants.

    PubMed

    Israeli, Eitan; Pardo, Asher

    2011-06-01

    Sick building syndrome (SBS) is a term coined for a set of clinically recognizable symptoms and ailments without a clear cause reported by occupants of a building. In the 1990s the term "functional somatic syndromes" was applied to several syndromes, including SBS, multiple chemical sensitivity, repetition stress injury, the side effects of silicone breast implants, the Gulf War syndrome (GWS), chronic fatigue syndrome, the irritable bowel syndrome, and fibromyalgia. Recently, Shoenfeld and Agmon-Levin suggested that four conditions--siliconosis, macrophagic myofascitis, the GWS, and post-vaccination phenomena--which share clinical and pathogenic resemblances, may be included under a common syndrome entitled the "autoimmune (auto-inflammatory) syndrome induced by adjuvants". Comparison of the clinical manifestations, symptoms, and signs of the four conditions described by Shoenfeld and Agmon-Levin with those described for SBS shows that nine out of ten main symptoms are present in all 5 conditions. Shoenfeld and Agmon-Levin further propose several major and minor criteria, which, although requiring further validation, may aid in the diagnosis of this newly defined syndrome. We propose here that SBS may also be included as a part of "Shoenfeld's syndrome".

  4. Amelioration of adjuvant-induced arthritis by ursolic acid through altered Th1/Th2 cytokine production.

    PubMed

    Ahmad, Sheikh Fayaz; Khan, Beenish; Bani, Sarang; Suri, K A; Satti, N K; Qazi, G N

    2006-03-01

    The objective of the study was to investigate the activity of ursolic acid (UA) on proinflammatory (Th1) and anti-inflammatory (Th2) cytokines in the peripheral blood of arthritic balb/c mice. Ursolic acid is ubiquitous in the plant kingdom and is a constituent of numerous plants which are having diversified phylogenetic origin and taxonomic position. We applied Cytometric bead array (CBA) technology for simultaneously measurement of these cytokines in adjuvant inflammatory arthritis induced mice treated with ursolic acid in graded oral doses. Cytometric bead array uses the sensitivity of amplified fluorescence detection by flowcytometer to measure soluble analytes in a particle based immune assay. This assay can accurately quantitate five cytokines in a 50 microl sample volume. The T-helper (Th1) deviated cells produce detectable level of tumor necrosis factor (TNF-alpha), interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), while the Th2 deviated cells produce significant amount of interleukin-4 (IL-4) and interleukin-5 (IL-5). Oral administration of UA at doses of 10, 20, 40, 80 and 160 mg kg(-1) per oral dose inhibited the presence of IL-2, IFN-gamma and TNF-alpha in the peripheral blood.

  5. Pseudo-Mannosylated DC-SIGN Ligands as Potential Adjuvants for HIV Vaccines

    PubMed Central

    Berzi, Angela; Varga, Norbert; Sattin, Sara; Antonazzo, Patrizio; Biasin, Mara; Cetin, Irene; Trabattoni, Daria; Bernardi, Anna; Clerici, Mario

    2014-01-01

    The development of new and effective adjuvants may play a fundamental role in improving HIV vaccine efficacy. New classes of vaccine adjuvants activate innate immunity receptors, notably toll like receptors (TLRs). Adjuvants targeting the C-Type lectin receptor DC-SIGN may be alternative or complementary to adjuvants based on TRL activation. Herein we evaluate the ability of the glycomimetic DC-SIGN ligand Polyman 19 (PM 19) to modulate innate immune responses. Results showed that PM 19 alone, or in combination with TLR agonists, induces the expression of cytokines, β chemokines and co-stimulatory molecules that may, in turn, modulate adaptive immunity and exert anti-viral effects. These results indicate that the suitability of this compound as a vaccine adjuvant should be further evaluated. PMID:24473338

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

    PubMed Central

    Martin, Hélène; Seguin-Py, Stéphanie; Maguin-Gaté, Katy; Moretto, Johnny; Totoson, Perle; Wendling, Daniel

    2017-01-01

    Objectives 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. Methods 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). Results 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. Conclusions 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. PMID:28759646

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

    PubMed Central

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

    2015-01-01

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

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

    USDA-ARS?s Scientific Manuscript database

    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...

  9. Evaluation of Acute Locoregional Toxicity in Patients With Breast Cancer Treated With Adjuvant Radiotherapy in Combination With Bevacizumab

    SciTech Connect

    Goyal, Sharad

    2011-02-01

    Purpose: Preclinical studies have shown that bevacizumab combined with radiotherapy (RT) induces a radiosensitizing effect. Published reports regarding the safety of combination therapy involving bevacizumab and RT are lacking. The purpose of this study was to analyze acute locoregional toxicity in patients with breast cancer receiving concurrent bevacizumab plus RT. Methods and Materials: After institutional review board approval was obtained, patients with breast cancer who received bevacizumab were identified; these patients were then cross-referenced with patients receiving RT. Toxicity was scored by the Common Terminology Criteria for Adverse Events. Patients were matched 1:1 with those who did not receive bevacizumab. Statistical analysis was performed to analyze toxicity between the two groups. Results: Fourteen patients were identified to have received bevacizumab plus RT. All patients receivedbevacizumab during RT without delay or treatment breaks; there were no RT treatment breaks in all patients. No patient receiving bevacizumab plus RT experienced {>=}Grade 3 toxicity; 3 matched control patients experienced a Grade 3 skin reaction. There was no difference in fatigue, radiation fibrosis, pneumonitis, or lymphedema between the two groups. Five patients (35%) developed reduction in ejection fraction; 2 with right-sided and 3 with left-sided treatment. Patients with left-sided treatment experienced a persistent reduction in ejection fraction compared with those receiving right-sided treatment. Conclusion: Concurrent bevacizumab and RT did not increase acute locoregional toxicity in comparison with matched control patients who did not receive RT alone. The addition of concurrent RT when treating the intact breast, chest wall, and associated nodal regions in breast cancer seems to be safe and well tolerated.

  10. Efficacy and safety of single agent or combination adjuvant chemotherapy in elderly patients with colon cancer: a Canadian cancer institute experience.

    PubMed

    Kim, Christina A K; Spratlin, Jennifer L; Armstrong, Dawn E; Ghosh, Sunita; Mulder, Karen E

    2014-09-01

    The pattern of adjuvant chemotherapy (AC) use, toxicity profile, and survival benefit in elderly patients with colon cancer (CC) is unclear. We sought to (1) determine whether patients ≥ 65 years with stage III CC were offered single-agent or combination AC, (2) evaluate the reason for selecting single-agent versus combination AC, (3) evaluate the toxicity profile of single-agent and combination AC in the elderly, and (4) determine whether a survival benefit exists for elderly patients receiving combination AC. A retrospective analysis of records of patients ≥ 65 years diagnosed with stage III CC from 2004 to 2010 was performed to identify baseline characteristics, AC protocols, toxicity, dose intensity, and survival. Two hundred sixty-eight patients ≥ 65 years were diagnosed and treated with AC from 2004 to 2010. Of these patients, 178 were treated with single-agent AC and 90 were treated with combination AC. The most common reasons for choosing single-agent AC were patient preference, comorbidities, and lack of drug coverage. For each year over 65 years, the odds of receiving combination over single-agent AC decreased by 22%. There were more dose delays, dose reductions, and early chemotherapy discontinuation in the combination AC group because of hematologic toxicity. The 5-year overall survival (OS) was 73% in patients who received single-agent AC compared with 84% in those who received combination AC. There was no difference in cancer-related deaths between the groups. In elderly patients treated with AC for stage III CC, single-agent AC is used more frequently than combination AC, based on age, comorbidities, and patient choice. Toxicity with combination AC in elderly patients is high. No survival benefit was seen with combination AC over single-agent AC. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. [Experimental food-induced fatty liver and its adjuvant therapy with natural bioactive substances].

    PubMed

    Hegedüs, Viktor; Gerö, Domokos; Mihály, Zoltán; Szijártó, Attila; Zelles, Tivadar; Sárdi, Eva

    2011-06-26

    Changes of redox-homeostasis generate cytokines, and free radicals influence many intracellular signaling pathways in different liver diseases. Liophylised table beet and carrot powder (GPS Powder Kft. 1361/004/2003BFÁÉÉÁ) containing bioactive components such as betaine, betanins, betaxanthins, flavonoids, polyphenols, glutamine, beta carotene, vitamins and folic acid may induce changes in various cellular pathways. The aim of this study was to determine the protecting effects of bioactive agents of the liophylised table beet and carrot powder on fatty liver in a "short term" experiment. Male Wistar rats were fed with chow with or without high fat (2% cholesterol, 0.5% cholic acid, 20% sunflower oil) and treated with 0.1 or 1 g/bwkg/day natural product for ten days parallel with the feedings. Cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-α mRNA levels were determined using molecular biologic methods. Free radicals, H-donating activity, reducing power and free SH-group concentrations were determined by luminometry and spectrophotometry. Mobilized methyl groups were assayed by high pressure liquid chromatography method in liver homogenates. It was found that the higher dose of the natural product better decreased the induced free radical reactions, cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-α mRNA-levels both in normal and fatty liver tissues. Although treatments failed to exert significant changes in all global antioxidant parameters, mobilized methyl group concentrations were higher after treatments in fatty liver. Favorable tendencies were also noted in the redox-homeostasis of the fatty liver after treatment. As expected, lyophylised table beet and carrot proved to be a "functional food" in rats with alimentary fat induced fatty liver. It cannot be ruled out that this beneficial effect may have clinical relevance.

  12. A sudden onset of a pseudo-neurological syndrome after HPV-16/18 AS04-adjuvated vaccine: might it be an autoimmune/inflammatory syndrome induced by adjuvants (ASIA) presenting as a somatoform disorder?

    PubMed

    Poddighe, Dimitri; Castelli, Lucia; Marseglia, Gian Luigi; Bruni, Paola

    2014-12-01

    In last centuries, vaccines reduced the incidence of several infectious diseases. In last decades, some vaccines aimed at preventing also some cancers, where viruses play a causative role. However, several adverse events have been described after vaccines, but a causal relationship has been established only in a minority of cases. Here, we describe a pseudo-neurological syndrome occurred shortly after the administration of the bivalent HPV vaccine. Some autoimmune disorders, including neurological demyelinating diseases, have been reported after HPV vaccines, but the patient showed no organic lesions. The patient was diagnosed as having a functional somatoform syndrome, which was supposed to be autoimmune/inflammatory syndrome induced by adjuvants (ASIA), seen the temporal link with vaccination and the presence of anti-phospholipid autoantibodies. Immunological mechanisms of vaccines-and of adjuvants-have not been completely elucidated yet, and although there is no evidence of statistical association with many post-vaccination events, a causal link with vaccine cannot be excluded in some individuals.

  13. Trichilia monadelpha bark extracts inhibit carrageenan-induced foot-oedema in the 7-day old chick and the oedema associated with adjuvant-induced arthritis in rats.

    PubMed

    Ainooson, G K; Owusu, G; Woode, E; Ansah, C; Annan, K

    2012-01-01

    Trichilia monadelpha (Thonn) JJ De Wilde (Meliaceae) bark extract is used in African traditional medicine for the management of various disease conditions including inflammatory disorders such as arthritis. The present study was undertaken to evaluate the anti-inflammatory properties of aqueous (TWE), alcoholic (TAE) and petroleum ether extract (TPEE) of T. monadelpha using the 7-day old chick-carrageenan footpad oedema (acute inflammation) and the adjuvant-induced arthritis model in rats (chronic inflammation). TWE and TPEE significantly inhibited the chick-carrageenan footpad oedema with maximal inhibitions of 57.79±3.92 and 63.83±12 respectively, but TAE did not. The reference anti-inflammatory drugs (diclofenac and dexamethasone) inhibited the chick-carrageenan-induced footpad oedema, with maximal inhibitions of 64.92±2.03 and 71.85±15.34 respectively. Furthermore, all the extracts and the reference anti-inflammatory agents (diclofenac, dexamethasone, methotrexate) inhibited the inflammatory oedema associated with adjuvant arthritis with maximal inhibitions of 64.41±5.56, 57.04±8.57, 62.18±2.56%, for TWE, TAE and TPEE respectively and 80.28±5.79, 85.75±2.96, 74.68±3.03% for diclofenac, dexamethasone and methotrexate respectively. Phytochemical screening of the plant bark confirmed the presence of a large array of plant constituents such as alkaloids, glycosides, flavonoids, saponins, steroids, tannins and terpenoids, all of which may be potential sources of phyto-antiinflammatory agents. In conclusion, our work suggests that T. monadelpha is a potential source of antiinflammatory agents.

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

    PubMed

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

    2015-03-17

    In the search for an effective vaccine against the human pathogen, Listeria monocytogenes (Listeria), gold glyconanoparticles (GNP) loaded with a listeriolysin O peptide LLO91-99 (GNP-LLO) were used to immunise mice, initially using a dendritic cell (DC) vaccine approach, but subsequently using a standard parenteral immunisation approach. To enhance vaccine immunogenicity a novel polysaccharide adjuvant based on delta inulin (Advax™) was also co-formulated with the GNP vaccine. Confirming previous results, DC loaded in vitro with GNP-LLO provided better protection against listeriosis than DC loaded in vitro using free LLO peptide. The immunogenicity of GNP-LLO loaded DC vaccines was further increased by addition of Advax™ adjuvant. However, as DC vaccines are expensive and impracticable for prophylactic use, we next asked whether the same GNP-LLO antigen could be used to directly target DC in vivo. Immunisation of mice with GNP-LLO plus Advax™ adjuvant induced LLO-specific T-cell immunity and protection against Listeria challenge. Protection correlated with an increased frequency of splenic CD4(+) and CD8(+) T cells, NK cells and CD8α(+) DC, and Th1 cytokine production (IL-12, IFN-γ, TNF-α, and MCP-1), post-challenge. Enhanced T-cell epitope recruitment post-challenge was seen in the groups that received Advax™ adjuvant. Immunisation with GNP-LLO91-99 plus Advax™ adjuvant provided equally robust Listeria protection as the best DC vaccine strategy but without the complexity and cost, making this a highly promising strategy for development of a prophylactic vaccine against listeriosis. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Chemotherapy-induced pain and neuropathy: a prospective study in patients treated with adjuvant oxaliplatin or docetaxel.

    PubMed

    Ventzel, Lise; Jensen, Anders B; Jensen, Anni R; Jensen, Troels S; Finnerup, Nanna B

    2016-03-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer therapy. This study evaluates symptoms of CIPN and CIPN-related pain and its influence on psychological functioning and potential predictors of chronic CIPN and pain. In this large prospective questionnaire study, 174 patients receiving adjuvant oxaliplatin or docetaxel were consecutively included. Patients were asked to complete a questionnaire with validated questions on peripheral neuropathy, pain, anxiety and depression, and quality of life at baseline, after the first cycle, halfway through therapy, and 1 year after baseline. Chronic CIPN symptoms (tingling and/or numbness) in the feet at 1-year follow-up were present in 63.6% of patients without preexisting neuropathy in the oxaliplatin group and in 44.8% in the docetaxel group, whereas pain in hands and feet was found in 31.3% and 35.1%, respectively. Both groups had significantly different pain profiles, and persistent pain in the docetaxel group was found to have effect on psychological function. Cumulative dose predicted oxaliplatin-induced neuropathy (P = 0.004), whereas endocrine therapy predicted peripheral pain in the docetaxel group (P = 0.04). There are important differences in acute neuropathic symptoms and chronic pain profiles in patients after oxaliplatin and docetaxel treatment. It is, however, important to recognize that chronic peripheral pain may be unrelated to neuropathy and can be caused by concomitant treatments. Future studies should focus on characterizing and distinguishing CIPN-related pain from other types of pain to determine the best outcome measures for trials on prevention or relief.

  16. Anti-inflammatory and immunomodulating properties of grape melanin. Inhibitory effects on paw edema and adjuvant induced disease.

    PubMed

    Avramidis, N; Kourounakis, A; Hadjipetrou, L; Senchuk, V

    1998-07-01

    Natural or synthetic melanin (CAS 8049-97-6) is a high molecular weight heteropolymer, product of the enzyme tyrosinase, found to possess radical scavenging and antioxidant functions. It was of interest, therefore, to study in detail the possible anti-inflammatory and/or immunosuppressive properties of a melanin isolated from grapes. The inhibitory effect of melanin on carrageenin-induced edema, as well as on edemas produced by other phlogistics, was remarkable suggesting that melanin interferes with the prostaglandin as well as the leukotriene and/or complement system mediated inflammation. Grape melanin showed potent inhibitory effect on adjuvant induced disease (AID) in rat, suppressing significantly the primary inflammation and almost totally the secondary lesions of arthritis. Melanin under the present experimental conditions not only strongly inhibited the in vitro lipid peroxidation of rat liver microsomal membranes, but furthermore protected the in vivo hepatic peroxidation occurring in AID rats, demonstrating its antioxidant and cytoprotective properties. The serum proinflammatory cytokines IL-1, IL-6 and TNF-a and the serum globulin fraction were elevated in AID rats, parameters which were more or less normalised by melanin treatment in contrast to the reduced serum levels of IL-2 which were not affected. Similarly to other lipoxygenase inhibitors and hydroxyl radical scavenger NSAIDs, melanin treatment did not affect IL-1 neither increased the splenic mitogenic responses, unlike the classical cyclooxygenase inhibitory NSAIDs. The subpopulation Th1 (T4+ or T8+) of lymphocytes is mainly responsible for cellular immune responses and thus their possible inhibition by melanin could lead to suppression of the development of AID, a model for cell-mediated immunity. The effect of melanin on T-cells is exhibited by the reduced spleen mitogenic responses to a T-cell mitogen and the reduced serum levels of IL-2 of treated rats. In conclusion, grape melanin is an

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

    PubMed Central

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

    2016-01-01

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

  18. Intranasal administration of a synthetic lipopeptide without adjuvant induces systemic immune responses

    PubMed Central

    Benmohamed, Lbachir; Krishnan, Radhika; Auge, Catherine; Primus, James F; Diamond, Don J

    2002-01-01

    Parenteral injection of a lipopeptide containing a human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T-lymphocyte (CTL) epitope from the human cytomegalovirus (HCMV) immunodominant matrix protein pp65 efficiently induces systemic CTL responses in HLA-A*0201 transgenic mice. In this study, we demonstrate that intranasal (i.n.) administration of this lipopeptide, covalently linked to a universal T helper (Th) epitope (PADRE), also induces potent systemic CTL responses. Immune responses were substantially reduced when the unlipidated peptide analogue was used (P<0·01). The induced CTL were CD8+, major histocompatibility complex (MHC) class I-restricted and CMV specific. Moreover, i.n. administration of this lipidated peptide elicited both systemic and local mucosal CD4+ T-cell proliferative responses, as well as antigen-specific delayed type hypersensitivity (DTH) immune responses. In contrast, mice receiving the unlipidated peptide analogue developed substantially reduced Th or DTH responses (P<0·05). These results highlight the usefulness and potential of lipopeptides delivered via mucosal routes as painless, safe, and non-invasive vaccines. PMID:11972639

  19. Assessments of Immunomodulatory and Inflammatory effects against Induction of Entamoeba histolytica (HM1 IMS strain) crude extract Antigen in Complete Freund's Adjuvant Induced Rheumatoid Arthritis Female Wistar Rats.

    PubMed

    Bagde, Swati; Singh, Vinod

    2015-01-01

    Today it is well known about mechanisms of cell communication, how the cells that mediate immune response and tissue injury accumulate in tissues but the aetiology of rheumatoid arthritis (RA) is still unknown. This study was to evaluate immunomodulatory effects of crude Entamoeba histolytica (HM1 IMS strain) antigen in complete freund's adjuvant female wistar rats by studying the alterations in humoral and cell mediated immune responses and also the inflammatory effects by evaluating the changes in body weight, paw thickness, biochemical, serological, interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α) and histopathology activities. Animals were randomly divided into six groups (n=6). CFA was induced in arthritic, drug and AA+CFA group whereas, 0.5ml amoebic antigen was induced subplantal in AA group while 0.5ml dose of amoebic antigen was given orally to AA+CFA group for 7-28th days. Indomethacin was used as a standard drug. Effects of amoebic antigen were associated with increased paw thickness and decreased body weight when compared to healthy control showed a significant difference. Oral administration of amoebic antigen has showed increased severe symptoms of arthritis in AA+CFA on comparison to healthy control rats. Significant increase in serum level of IL-6 and α TNF were found in AA group followed by AA+CFA group whereas, decrease in concentration of IL-10 was appear in AA+CFA group on comparison to arthritic and healthy control group (P<0.05). Histopathology of AA group showed severe signs of necrotic and degenerative changes on comparison to healthy control group. Thus the results demonstrated that E. histolytica alone or in combination with CFA increased bone damage, with alterations in antioxidant level in liver and kidney tissue homogenates as well as showed immunomodulatory arthritogenic properties which may contribute and raise joint inflammation.

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

    PubMed Central

    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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-05-01

    A vaccine to prevent the transmission of malaria parasites from infected humans to mosquitoes is an important component for the elimination of malaria in the 21st century, yet it remains neglected as a priority of malaria vaccine development. The lead candidate for Plasmodium falciparum transmission-blocking vaccine development, Pfs25, is a sexual stage surface protein that has been produced for vaccine testing in a variety of heterologous expression systems. Any realistic malaria vaccine will need to optimize proper folding balanced against cost of production, yield, and potentially reactogenic contaminants. Here Chlamydomonas reinhardtii microalga-produced recombinant Pfs25 protein was formulated with four different human-compatible adjuvants (alum, Toll-like receptor 4 [TLR-4] agonist glucopyranosal lipid A [GLA] plus alum, squalene-oil-in-water emulsion, and GLA plus squalene-oil-in-water emulsion) and compared for their ability to induce malaria transmission-blocking antibodies. Alga-produced recombinant Pfs25 plus GLA plus squalene-oil-in-water adjuvant induced the highest titer and avidity in IgG antibodies, measured using alga-produced recombinant Pfs25 as the enzyme-linked immunosorbent assay (ELISA) antigen. These antibodies specifically reacted with the surface of P. falciparum macrogametes and zygotes and effectively prevented parasites from developing within the mosquito vector in standard membrane feeding assays. Alga-produced Pfs25 in combination with a human-compatible adjuvant composed of a TLR-4 agonist in a squalene-oil-in-water emulsion is an attractive new vaccine candidate that merits head-to-head comparison with other modalities of vaccine production and administration. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  3. [The Clinical Utility of Pegfilgrastim in Combination with Adjuvant FEC(100)and TC Chemotherapy for Breast Cancer].

    PubMed

    Yanai, Hirotsugu; Endo, Kayoko; Matsumoto, Mayumi; Kon, Masanori; Sugie, Tomoharu

    2016-09-01

    More than 20%of breast cancer patients who undergo myelosuppressive chemotherapy involving FEC(100) or TC experience febrile neutropenia(FN), and pegfilgrastim is commonly recommended as the primary prophylaxis. Delays and/or dose-reductions in chemotherapy should be avoided as much as possible to maximize the clinical benefits of these adjuvant chemotherapies. This study assessed the relative dose intensity(RDI), efficacy, and safety of pegfilgrastim in patients with breast cancer. The incidence of FN was also evaluated. Twenty-six patients with breast cancer undergoing FEC(100)or TC were included in this retrospective study. Of the 26 patients, 19 patients who underwent FEC(100)and 7 patients who underwent TC received 3.6 mg of pegfilgrastim 24 hours after administration of the myelosuppressive chemotherapy. Four and 14 patients who underwent FEC(100)achieved 85-99% and 100% RDI, respectively. All 7 patients who underwent TC achieved 100% RDI. Grade 3 and 4 adverse events, as assessed using the CTCAE, were observed in 11 patients who underwent FEC(100): 2 patients experienced leukocytopenia, 7 experienced neutropenia, 1 experienced thrombocytopenia, and 1 experienced FN. Four patients who underwent TC experienced Grade 3 and 4 adverse events: 1 patient each experienced bone pain, neutropenia, anemia, and FN. Pegfilgrastim can reduce the incidence of FN and maintain RDI in patients with breast cancer undergoing myelosuppressive chemotherapy.

  4. Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: prognostic role and clinical implications.

    PubMed

    Del Mastro, L; Venturini, M; Sertoli, M R; Rosso, R

    1997-04-01

    The role of amenorrhea induced by chemotherapy in premenopausal women with early breast cancer is very controversial. Analyses by various authors of the effect of drug-induced amenorrhea (DIA) on treatment outcome have yielded conflicting results. In order to gain insight into the role of DIA, we reviewed all published data addressing the issue of DIA as a prognostic factor. Computerised and manual searches were conducted of relevant studies published from 1966 to 1995. Thirteen studies involving 3929 patients were selected. In two papers, the prognostic role of DIA was analysed in three and two different groups of patients, respectively. Overall, 16 groups of patients were evaluated. With 12 groups, a higher disease free survival was observed in patients developing DIA compared to those who did not. This difference was statistically significant in eight groups. Data on overall survival, reported in only five studies, indicated that it was always improved in patients who became amenorrheic. Available data on the role of DIA support its importance as a favorable prognostic factor for early breast cancer patients. However, due to the possible biases of this type of evaluation, this result should be interpreted with caution.

  5. Fusion of antigen to a dendritic cell targeting chemokine combined with adjuvant yields a malaria DNA vaccine with enhanced protective capabilities.

    PubMed

    Luo, Kun; Zhang, Hong; Zavala, Fidel; Biragyn, Arya; Espinosa, Diego A; Markham, Richard B

    2014-01-01

    Although sterilizing immunity to malaria can be elicited by irradiated sporozoite vaccination, no clinically practical subunit vaccine has been shown to be capable of preventing the approximately 600,000 annual deaths attributed to this infection. DNA vaccines offer several potential advantages for a disease that primarily affects the developing world, but new approaches are needed to improve the immunogenicity of these vaccines. By using a novel, lipid-based adjuvant, Vaxfectin, to attract immune cells to the immunization site, in combination with an antigen-chemokine DNA construct designed to target antigen to immature dendritic cells, we elicited a humoral immune response that provided sterilizing immunity to malaria challenge in a mouse model system. The chemokine, MIP3αCCL20, did not significantly enhance the cellular infiltrate or levels of cytokine or chemokine expression at the immunization site but acted with Vaxfectin to reduce liver stage malaria infection by orders of magnitude compared to vaccine constructs lacking the chemokine component. The levels of protection achieved were equivalent to those observed with irradiated sporozoites, a candidate vaccine undergoing development for further large scale clinical trial. Only vaccination with the combined regimen of adjuvant and chemokine provided 80-100% protection against the development of bloodstream infection. Treating the immunization process as requiring the independent steps of 1) attracting antigen-presenting cells to the site of immunization and 2) specifically directing vaccine antigen to the immature dendritic cells that initiate the adaptive immune response may provide a rational strategy for the development of a clinically applicable malaria DNA vaccine.

  6. Fusion of Antigen to a Dendritic Cell Targeting Chemokine Combined with Adjuvant Yields a Malaria DNA Vaccine with Enhanced Protective Capabilities

    PubMed Central

    Luo, Kun; Zhang, Hong; Zavala, Fidel; Biragyn, Arya; Espinosa, Diego A.; Markham, Richard B.

    2014-01-01

    Although sterilizing immunity to malaria can be elicited by irradiated sporozoite vaccination, no clinically practical subunit vaccine has been shown to be capable of preventing the approximately 600,000 annual deaths attributed to this infection. DNA vaccines offer several potential advantages for a disease that primarily affects the developing world, but new approaches are needed to improve the immunogenicity of these vaccines. By using a novel, lipid-based adjuvant, Vaxfectin, to attract immune cells to the immunization site, in combination with an antigen-chemokine DNA construct designed to target antigen to immature dendritic cells, we elicited a humoral immune response that provided sterilizing immunity to malaria challenge in a mouse model system. The chemokine, MIP3αCCL20, did not significantly enhance the cellular infiltrate or levels of cytokine or chemokine expression at the immunization site but acted with Vaxfectin to reduce liver stage malaria infection by orders of magnitude compared to vaccine constructs lacking the chemokine component. The levels of protection achieved were equivalent to those observed with irradiated sporozoites, a candidate vaccine undergoing development for further large scale clinical trial. Only vaccination with the combined regimen of adjuvant and chemokine provided 80–100% protection against the development of bloodstream infection. Treating the immunization process as requiring the independent steps of 1) attracting antigen-presenting cells to the site of immunization and 2) specifically directing vaccine antigen to the immature dendritic cells that initiate the adaptive immune response may provide a rational strategy for the development of a clinically applicable malaria DNA vaccine. PMID:24599116

  7. Phase II Trial of Adjuvant Pelvic Radiation “Sandwiched” Between Combination Paclitaxel and Carboplatin in Women with Uterine Papillary Serous Carcinoma

    PubMed Central

    Einstein, Mark H.; Frimer, Marina; Kuo, Dennis Y-S; Reimers, Laura L.; Mehta, Keyur; Mutyala, Subhakar; Huang, Gloria S.; Hou, June Y.; Goldberg, Gary L.

    2013-01-01

    Objective To evaluate the safety and survival in women treated with adjuvant pelvic radiation “sandwiched” between six cycles of paclitaxel and carboplatin chemotherapy with completely resected UPSC. Methods Surgically staged women with UPSC (FIGO stage 1-4) and no visible residual disease were enrolled. Treatment involved paclitaxel (175 mg/m2) and carboplatin (AUC=6.0-7.5) every 21 days for 3 doses, followed by radiation therapy (RT), followed by an additional 3 cycles of paclitaxel and carboplatin (AUC=5-6). Survival analysis, using Kaplan-Meier methods, was performed on patients who completed at least 3 cycles of chemotherapy and RT. Results A total of 81 patients were enrolled, of which 72 patients completed the first 3 cycles of chemotherapy followed by prescribed RT. Median age was 67 years (range: 43–82 years). 59/72 (82%) had disease confined to the uterus and 13/72 (18%) had completely resected extra-uterine disease (stage 3&4). 65 (83%) completed the protocol. Overall PFS and OS for combined stage 1&2 patients was 65.5±3.6 months and 76.5±4.3 months, respectively. PFS and OS for combined stage 3&4 patients was 25.8±3.0 and 35.9±5.3 months, respectively. Three-year % survival probability for stage 1&2 patients was 84% and for stage 3&4 patients was 50%. Of the 435 chemotherapy cycles administered, there were 11(2.5%) G3/G4 non-hematologic toxicities. 26(6.0%) cycles had dose reductions and 37(8.5%) had dose delays. Conclusions Compared to prior studies of single modality adjuvant therapy, RT “sandwiched” between paclitaxel and carboplatin chemotherapy is well-tolerated and highly efficacious in women with completely resected UPSC. PMID:22035806

  8. Molecular signatures of vaccine adjuvants.

    PubMed

    Olafsdottir, Thorunn; Lindqvist, Madelene; Harandi, Ali M

    2015-09-29

    Mass vaccination has saved millions of human lives and improved the quality of life in both developing and developed countries. The emergence of new pathogens and inadequate protection conferred by some of the existing vaccines such as vaccines for tuberculosis, influenza and pertussis especially in certain age groups have resulted in a move from empirically developed vaccines toward more pathogen tailored and rationally engineered vaccines. A deeper understanding of the interaction of innate and adaptive immunity at molecular level enables the development of vaccines that selectively target certain type of immune responses without excessive reactogenicity. Adjuvants constitute an imperative element of modern vaccines. Although a variety of candidate adjuvants have been evaluated in the past few decades, only a limited number of vaccine adjuvants are currently available for human use. A better understanding of the mode of action of adjuvants is pivotal to harness the potential of existing and new adjuvants in shaping a desired immune response. Recent advancement in systems biology powered by the emerging cutting edge omics technology has led to the identification of molecular signatures rapidly induced after vaccination in the blood that correlate and predict a later protective immune response or vaccine safety. This can pave ways to prospectively determine the potency and safety of vaccines and adjuvants. This review is intended to highlight the importance of big data analysis in advancing our understanding of the mechanisms of actions of adjuvants to inform rational development of future human vaccines.

  9. The Mincle-Activating Adjuvant TDB Induces MyD88-Dependent Th1 and Th17 Responses through IL-1R Signaling

    PubMed Central

    Desel, Christiane; Werninghaus, Kerstin; Ritter, Manuel; Jozefowski, Katrin; Wenzel, Jens; Russkamp, Norman; Schleicher, Ulrike; Christensen, Dennis; Wirtz, Stefan; Kirschning, Carsten; Agger, Else Marie; da Costa, Clarissa Prazeres; Lang, Roland

    2013-01-01

    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. PMID:23308247

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

    PubMed Central

    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

  11. Studies on respiratory immunization with tetanus toxoid: the role of adjuvants.

    PubMed

    Bartlema, H C; Braunius, R; Hölscher, L

    1972-12-01

    Aerosol vaccination of mice with purified plain tetanus toxoid does not induce an immune response unless a suitable adjuvant is added.Aluminium phosphate is without effect by aerosol treatment. Killed cells of Klebsiella pneumoniae, although effective, are unsatisfactory owing to the long inhalation period needed.Killed Bordetella perussis cells were found to be an excellent adjuvant. A single aerosol treatment with a toxoid-B. pertussis mixture during a moderate exposure period evoked a considerable immune response. With repeated aerosol treatment of primed mice the addition of adjuvant is not required; booster treatment with plain toxoid is at least as effective.Extracts from B. pertussis cells exert as good an adjuvant effect as the whole-cell vaccine. The remaining cell-wall debris also appears to be an active adjuvant.In combination with constant doses of adjuvant (10(8)B. pertussis cells), the 50% protective doses (ED 50) of toxoid were determined by inhalation and by s.c. injection and were found to be 0.1875 and 0.0625 LFU respectively. This would imply that, as a result of the adjuvant action, the s.c. ED 50 is reduced by approximately a factor of 20; whereas the respiratory ED 50 is decreased by at least a factor of 100.It is suggested that the much more pronounced adjuvant activity in aerosol immunization is associated with the induction of strong cell-mediated hypersensitivity in the respiratory tract.

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

    PubMed

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

    2014-11-28

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

  13. Preclinical efficacy of sodium narcistatin to reduce inflammation and joint destruction in rats with adjuvant-induced arthritis.

    PubMed

    Lubahn, Cheri; Schaller, Jill A; Shewmacker, Eric; Wood, Carlo; Bellinger, Denise L; Byron, Donna; Melody, Noeleen; Pettit, George R; Lorton, Dianne

    2012-12-01

    Current therapies for the treatment of rheumatoid arthritis (RA) do not work for all patients, can lose efficacy over time, and can have significant side effects. The discovery of new, effective therapies for RA remains an unmet medical need. The Amaryllidaceae isocarbostyril narciclasine was previously shown to prophylactically reduce paw swelling in rats with adjuvant-induced arthritis (AA). In this study, the efficacy of sodium narcistatin (SNS), a water-soluble cyclic phosphate pro-drug of narciclasine, was assessed in AA rats for anti-inflammatory and bone-sparing properties after disease onset. AA rats were given daily intraperitoneal injections of SNS (1.75, 3.5, or 5 mg/kg/day, in 500 μl sterile endotoxin-free saline) or saline from disease onset through severe disease stages. Footpad widths and radiographic scoring were used as indicators of inflammation and joint destruction, respectively. Ex vivo cytokine production by peripheral blood mononuclear cells (PMBC), splenocytes, and draining lymph node (DLN) cells were determined using ELISAs. SNS treatment dose-dependently reduced joint inflammation (~70%) and bone loss (~50%) compared with AA controls. SNS treatment also reduced spleen weight (without affecting body weight), pro-inflammatory cytokine production by PMBC, splenocytes, and DLN cells, and site-dependently altered T-helper (Th)1-/Th2-type and anti-inflammatory cytokine profiles. SNS dramatically reduces inflammation and has bone-sparing properties, possibly by reducing immune cell pro-inflammatory cytokine production. Our findings support the development of SNS as a therapeutic for RA.

  14. Green tea extract improves the oxidative state of the liver and brain in rats with adjuvant-induced arthritis.

    PubMed

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

    2015-08-01

    The purpose of the study was to evaluate the possible effects of the administration of a green tea extract on the oxidative state of the liver and brain of adjuvant-induced arthritic rats, a model for human rheumatoid arthritis. Daily doses of 250 mg kg(-1) (59.8 mg catechins per kg) for 23 days were administered. This treatment produced significant diminutions in protein and lipid damage in liver, brain and plasma. It also diminished the tissue ROS contents and increased the antioxidant capacity of the plasma. The antioxidant defenses, which are diminished by arthritis, were improved by the green tea treatment, as revealed by the restoration of the GSH and protein thiol levels and by the strong tendency for normalizing the activities of the antioxidant enzymes. The activity of glucose 6-phosphate dehydrogenase, which is increased by arthritis in the liver, was also almost normalized by the treatment. In conclusion, it can be said that green tea consumption is possibly beneficial for the liver and brain of patients suffering from rheumatoid arthritis because it attenuates the pronounced oxidative stress that accompanies the disease and, thus, diminishes the injury to lipids and proteins in both liver and brain. There are also indications that, in the liver, the green tea can contribute to normalize the metabolic functions that are substantially modified by arthritis. For example, the green tea normalized the activity of glucose 6-phosphate dehydrogenase, a key enzyme of an important metabolic route (pentose monophosphate pathway). It is expected that the green tea treatment is equally able to normalize the activity of other enzymes (e.g., glucokinase and glucose 6-phosphatase), a hypothesis to be tested by future work.

  15. Genetic Predictors of Taxane-induced Neurotoxicity in a SWOG Phase III Intergroup Adjuvant Breast Cancer Treatment Trial (S0221)

    PubMed Central

    Sucheston, Lara E.; Zhao, Hua; Yao, Song; Zirpoli, Gary; Liu, Song; Barlow, William E.; Budd, G. Thomas; Hershman, Dawn L.; Davis, Warren; Ciupak, Gregory L.; Stewart, James A.; Isaacs, Claudine; Hobday, Timothy J.; Salim, Muhammad; Hortobagyi, Gabriel N.; Gralow, Julie R.; Livingston, Robert B.; Albain, Kathy S.; Hayes, Daniel F.; Ambrosone, Christine B.

    2012-01-01

    Purpose We assessed SNPS in the Fanconi Anemia (FA)/BRCA pathway in women being was taxanes for breast cancer in an effort to find a prognostic biomarker for neurological toxicities, which while improve survival remain a debilitating outcome. Patients and Methods We used data and samples (n=888) from SWOG0221, a phase III adjuvant trial of 4 dose/schedules of cyclophosphamide (C), doxorubicin (A) and paclitaxel (T) for high risk breast cancer. The relationship of SNPs in the (FA)/BRCA pathway with risk grade 3/4 neurotoxicities. In a separate cohort we measured the correlation of significant SNPs in this pathway with corresponding gene expression. Results No associations between SNPs in BRCA1 and taxane-induced neuropathy was found. For FANCD2, significant associations between 4 (out of 20) SNPs and neurological toxicities, with risk estimates approaching 2. Two FANCD2 haplotypes were also found to be significantly associated with neurological toxicity, increasing the odds in the overall population 1.8 (95% confidence interval (CI) 1.3–2.5) and 1.7 (95% CI, 1.2–2.4) fold. Although numbers were small, there appeared to be a specific African-American haplotype that was associated with an almost 3-fold increase in risk of neurological toxicity. Expression analyses revealed that significant FANCD2 SNPs were associated with FANCD2 expression levels (p=0.03) Conclusion SNPs in FANCD2, were associated with a 70 to 80% increase in the odds of grade 3/4 neurological toxicities and increased expression of the gene. If replicated, women with these genotypes should be closely monitored for toxicities, and could be targeted for preventive measures or alternative therapeutic approaches. PMID:21766209

  16. Human papilloma virus vaccine and primary ovarian failure: another facet of the autoimmune/inflammatory syndrome induced by adjuvants.

    PubMed

    Colafrancesco, Serena; Perricone, Carlo; Tomljenovic, Lucija; Shoenfeld, Yehuda

    2013-10-01

    Post-vaccination autoimmune phenomena are a major facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and different vaccines, including HPV, have been identified as possible causes. The medical history of three young women who presented with secondary amenorrhea following HPV vaccination was collected. Data regarding type of vaccine, number of vaccination, personal, clinical and serological features, as well as response to treatments were analyzed. All three patients developed secondary amenorrhea following HPV vaccinations, which did not resolve upon treatment with hormone replacement therapies. In all three cases sexual development was normal and genetic screen revealed no pertinent abnormalities (i.e., Turner's syndrome, Fragile X test were all negative). Serological evaluations showed low levels of estradiol and increased FSH and LH and in two cases, specific auto-antibodies were detected (antiovarian and anti thyroid), suggesting that the HPV vaccine triggered an autoimmune response. Pelvic ultrasound did not reveal any abnormalities in any of the three cases. All three patients experienced a range of common non-specific post-vaccine symptoms including nausea, headache, sleep disturbances, arthralgia and a range of cognitive and psychiatric disturbances. According to these clinical features, a diagnosis of primary ovarian failure (POF) was determined which also fulfilled the required criteria for the ASIA syndrome. We documented here the evidence of the potential of the HPV vaccine to trigger a life-disabling autoimmune condition. The increasing number of similar reports of post HPV vaccine-linked autoimmunity and the uncertainty of long-term clinical benefits of HPV vaccination are a matter of public health that warrants further rigorous inquiry. © 2013 John Wiley & Sons Ltd.

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

    PubMed

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

    2013-12-01

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

  18. Topical therapies for rheumatoid arthritis by gel ointments containing indomethacin nanoparticles in adjuvant-induced arthritis rat.

    PubMed

    Nagai, Noriaki; Yoshioka, Chiaki; Ito, Yoshimasa

    2015-01-01

    Indomethacin (IMC), a nonsteroidal anti-inflammatory drug, has been used in the treatment of rheumatoid arthritis (RA), although its clinical use has been limited by its systemic side effects that include gastrointestinal lesions. Therefore, the development of IMC formulations that do not cause gastrointestinal lesions is highly anticipated. In this study, we designed new topical formulations containing IMC solid nanoparticles (IMCnano gel ointment), and investigated their pharmacokinetics. In addition, we demonstrate the preventive effects of this topical application of IMC nanoparticles on inflammation in adjuvant-induced arthritis rat (AA rat). The IMCnano gel ointment was prepared using Bead Smash 12 (a bead mill) and additives including 2-hydroxypropyl-β-cyclodextrin, methylcellulose and Carbopol 934; the mean particle size of the IMC nanoparticles was 173 ± 91 nm (means ± S.D.). The application of the IMCnano gel ointment attenuated the increase in paw edema of the hind feet of AA rats in comparison with AA rats treated with gel ointment containing IMC microparticles (IMCmicro gel ointment, particle diameter 17.1 ± 11.6 mm, means ± S.D). In addition, the accumulation of IMC from the IMCnano gel ointment in skin tissue was significantly large than for the IMCmicro gel ointment; however, the plasma IMC concentrations were similar for the IMCmicro and IMCnano gel ointments. Our findings suggest that the dermal application of nanoparticles may enable a medication to be applied without high-systemic drug levels, which could provide efficient and effective therapy that spares patients from unwanted side effects. A formulation of a topical drug delivery system using IMC nanoparticles may provide a delivery option for the clinical treatment of RA.

  19. Therapeutic effects of gel ointments containing tranilast nanoparticles on paw edema in adjuvant-induced arthritis rats.

    PubMed

    Nagai, Noriaki; Ito, Yoshimasa

    2014-01-01

    Tranilast (TL), an antiallergic agent, has been clinically used in the treatment of bronchial asthma, although its clinical use has been limited by its poor solubility in water, photodegradation and systemic side effects. In this study, we prepared a gel ointment containing TL nanoparticles (TLnano gel ointment), and investigated its usefulness. In addition, we demonstrated the preventive effects of the TLnano gel ointment on inflammation in adjuvant-induced arthritis (AA) rats. The TLnano gel ointment was prepared using Bead Smash 12 (a bead mill) and additives including sodium docusate, 2-hydroxypropyl-β-cyclodextrin, methylcellulose and Carbopol 934; the mean particle diameter of the TL nanoparticles was 71.0±25.4 nm. In in vitro skin penetration experiments, the amount of penetrated TL, the penetration rate (Jc) and the penetration coefficient through the skin (Kp) of the TLnano gel ointment were significantly higher than those of a gel ointment containing TL microparticles (TLmicro gel ointment; particle diameter 50.5±26.3 µm). The TL concentrations in the skin tissue and plasma of rats receiving the TLnano gel ointment were also higher than in rats receiving the TLmicro gel ointment. In addition, the application of the TLnano gel ointment attenuated the increase in paw edema of the hind feet of AA rats in comparison with AA rats treated with the TLmicro gel ointment. These results suggest that TL nanoparticles can be applied to the formulation of a transdermal system, and that a transdermal formulation using TL nanoparticles might be a delivery option for the clinical treatment of RA.

  20. Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors

    PubMed Central

    Tietz, Alexandra; Rahbari, Nuh N.; Bork, Ulrich; Schmidt, Thomas; Kahlert, Christoph; Haberkorn, Uwe; Tomai, Mark A.; Lipson, Kenneth E.; Carretero, Rafael; Weitz, Jürgen; Koch, Moritz; Huber, Peter E.

    2015-01-01

    In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy. PMID:25609199

  1. Mucosally induced immunological tolerance, regulatory T cells and the adjuvant effect by cholera toxin B subunit.

    PubMed

    Sun, J-B; Czerkinsky, C; Holmgren, J

    2010-01-01

    Induction of peripheral immunological tolerance by mucosal administration of selected antigens (Ags) ('oral tolerance') is an attractive, yet medically little developed, approach to prevent or treat selected autoimmune or allergic disorders. A highly effective way to maximize oral tolerance induction for immunotherapeutic purposes is to administer the relevant Ag together with, and preferably linked to the non-toxic B subunit protein of cholera toxin (CTB). Oral, nasal or sublingual administration of such Ag/CTB conjugates or gene fusion proteins have been found to induce tolerance with superior efficiency compared with administration of Ag alone, including the suppression of various autoimmune disorders and allergies in animal models. In a proof-of-concept clinical trial in patients with Behcet's disease, this was extended with highly promising results to prevent relapse of autoimmune uveitis. Tolerization by mucosal Ag/CTB administration results in a strong increase in Ag-specific regulatory CD4(+) T cells, apparently via two separate pathways: one using B cells as APCs and leading to a strong expansion of Foxp3(+) Treg cells which can both suppress and mediate apoptotic depletion of effector T cells, and one being B cell-independent and associated with development of Foxp3(-) regulatory T cells that express membrane latency-associated peptide and transforming growth factor (TGF-beta) and/or IL-10. The ability of CTB to dramatically increase mucosal Ag uptake and presentation by different APCs through binding to GM1 ganglioside (which makes most B cells effective APCs irrespective of their Ag specificity), together with CTB-mediated stimulation of TGF-beta and IL-10 production and inhibition of IL-6 formation may explain the dramatic potentiation of oral tolerance by mucosal Ags presented with CTB.

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  4. Development and Characterization of Synthetic Glucopyranosyl Lipid Adjuvant System as a Vaccine Adjuvant

    PubMed Central

    Moutaftsi, Magdalini; Guderian, Jeff A.; Windish, Hillarie Plessner; Baldwin, Susan L.; Laughlin, Elsa M.; Duthie, Malcolm S.; Fox, Christopher B.; Carter, Darrick; Friede, Martin; Vedvick, Thomas S.; Reed, Steven G.

    2011-01-01

    Innate immune responses to vaccine adjuvants based on lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, are driven by Toll-like receptor (TLR) 4 and adaptor proteins including MyD88 and TRIF, leading to the production of inflammatory cytokines, type I interferons, and chemokines. We report here on the characterization of a synthetic hexaacylated lipid A derivative, denoted as glucopyranosyl lipid adjuvant (GLA). We assessed the effects of GLA on murine and human dendritic cells (DC) by combining microarray, mRNA and protein multiplex assays and flow cytometry analyses. We demonstrate that GLA has multifunctional immunomodulatory activity similar to naturally-derived monophosphory lipid A (MPL) on murine DC, including the production of inflammatory cytokines, chemokines, DC maturation and antigen-presenting functions. In contrast, hexaacylated GLA was overall more potent on a molar basis than heterogeneous MPL when tested on human DC and peripheral blood mononuclear cells (PBMC). When administered in vivo, GLA enhanced the immunogenicity of co-administered recombinant antigens, producing strong cell-mediated immunity and a qualitative TH1 response. We conclude that the GLA adjuvant stimulates and directs innate and adaptive immune responses by inducing DC maturation and the concomitant release of pro-inflammatory cytokines and chemokines associated with immune cell trafficking, activities which have important implications for the development of future vaccine adjuvants. PMID:21298114

  5. Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant.

    PubMed

    Coler, Rhea N; Bertholet, Sylvie; Moutaftsi, Magdalini; Guderian, Jeff A; Windish, Hillarie Plessner; Baldwin, Susan L; Laughlin, Elsa M; Duthie, Malcolm S; Fox, Christopher B; Carter, Darrick; Friede, Martin; Vedvick, Thomas S; Reed, Steven G

    2011-01-26

    Innate immune responses to vaccine adjuvants based on lipopolysaccharide (LPS), a component of gram-negative bacterial cell walls, are driven by Toll-like receptor (TLR) 4 and adaptor proteins including MyD88 and TRIF, leading to the production of inflammatory cytokines, type I interferons, and chemokines. We report here on the characterization of a synthetic hexaacylated lipid A derivative, denoted as glucopyranosyl lipid adjuvant (GLA). We assessed the effects of GLA on murine and human dendritic cells (DC) by combining microarray, mRNA and protein multiplex assays and flow cytometry analyses. We demonstrate that GLA has multifunctional immunomodulatory activity similar to naturally-derived monophosphory lipid A (MPL) on murine DC, including the production of inflammatory cytokines, chemokines, DC maturation and antigen-presenting functions. In contrast, hexaacylated GLA was overall more potent on a molar basis than heterogeneous MPL when tested on human DC and peripheral blood mononuclear cells (PBMC). When administered in vivo, GLA enhanced the immunogenicity of co-administered recombinant antigens, producing strong cell-mediated immunity and a qualitative T(H)1 response. We conclude that the GLA adjuvant stimulates and directs innate and adaptive immune responses by inducing DC maturation and the concomitant release of pro-inflammatory cytokines and chemokines associated with immune cell trafficking, activities which have important implications for the development of future vaccine adjuvants.

  6. Diurnal rhythms in ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis in submaxillary lymph nodes and spleen of young and aged rats during Freund's adjuvant-induced arthritis.

    PubMed

    Cardinali, D P; Brusco, L I; Selgas, L; Esquifino, A I

    1998-04-13

    Aging has been associated with attenuation of amplitude and changes in period of many circadian rhythms. The present study was carried out to examine, in young (50 days old) and old (18 months old) rats, whether 24-h rhythms of cell proliferation (as assessed by measuring ornithine decarboxylase activity) and of presynaptic adrenergic and cholinergic markers change in lymph nodes and spleen during Freund's adjuvant-induced arthritis. Groups of young and old Sprague-Dawley rats were studied the day before, and on days 6, 12 and 18 after Freund's adjuvant injection. On day 16 after adjuvant injection, inflammation of hind paws, mainly in the ankle joints, was less marked in old than in young rats. Lymph node and splenic ornithine decarboxylase activity exhibited significant 24-h variations with maximal activity during daily hours. Before treatment, enzyme activity values were significantly lower in old rats in both tissues examined. During the immune reaction, lymph node and splenic ornithine decarboxylase augmented 8-10-fold, with progressively smaller amplitude of daily variations as arthritis developed. In every case, mesor and amplitude of ornithine decarboxylase activity were lowest in old rats. Submaxillary lymph node and splenic tyrosine hydroxylase activity attained maximal values at night. At every time interval after mycobacterium adjuvant injection, amplitude and mesor of tyrosine hydroxylase activity rhythm were lowest in old rats. A maximum in submaxillary lymph node 3H-acetylcholine synthesis occurred at the afternoon. On day 6 and 12 after Freund's adjuvant injection, lymph node 3H-acetylcholine synthesis was significantly smaller in old rats. Day-night differences in submaxillary lymph node or splenic ornithine decarboxylase and tyrosine hydroxylase activities, or in submaxillary lymph node 3H-acetylcholine synthesis, of rats treated with the adjuvant's vehicle, did not differ significantly from those seen in untreated controls. The results are

  7. Hormone therapy/adjuvant chemotherapy induced deleterious effects on the bone mass of breast cancer patients and the intervention of physiotherapy: a literature review.

    PubMed

    Tonezzer, T; Pereira, C M A P; Filho, U P; Marx, A

    2010-01-01

    In recent years, breast cancer has witnessed some notable improvements regarding early diagnosis and new therapeutical strategies, mainly because of the utilization of new drugs and systemic treatment protocols, which have had a direct impact in the increase of these patients' global survival rate. At the same time, it is an ever-growing concern among oncology professionals to identify and minimize as much as possible the effects of long-term toxicity resulting from cancer therapies. Within this context, physiotherapy fits as a preventive and rehabilitating factor regarding functional and skeletal alterations, deriving not only from the direct action of breast cancer, but also from the treatment to which these patients are submitted. The aim of this study was to revise the scientific literature on possible adjuvant chemotherapy-induced secondary deleterious effects on the bone mass of patients diagnosed with breast cancer, and also to revise the literature on the intervention of physiotherapy in cases of secondary bone mass loss caused by adjuvant chemotherapy in patients suffering from breast cancer. The research was carried out by consulting the following medical websites: Medicus Medline Index, Lilacs, Sciello, PubMed (National Library of Medicine), Google Academic and Capes (a Brazilian website for scientific information). The selection gathers articles written in different languages, English in special, published from January 1998 to October 2008. 24 studies explicitly mention chemotherapy-induced direct and/or indirect effects upon bone mass. Different authors refer to bone mass loss as one possible secondary deleterious effect resulting from adjuvant chemotherapy applied in breast cancer treatment. Nonetheless, no scientific articles were found on the subject of physiotherapy intervention aimed at patients in this specific condition. The results achieved in this revision study point out the possible chemotherapy-induced late deleterious effects on patients

  8. Sinomenine decreases MyD88 expression and improves inflammation-induced joint damage progression and symptoms in rat adjuvant-induced arthritis.

    PubMed

    Mu, Hui; Yao, Ru-Bing; Zhao, Ling-Jie; Shen, Si-Yu; Zhao, Zhi-Ming; Cai, Hui

    2013-10-01

    Sinomenine (SIN) is the active principle of the Chinese medical plant Sinomenium acutum which is widely used for the treatment of rheumatoid arthritis (RA) in China. Recently, several groups indicated that myeloid differentiation primary response protein 88 (MyD88) might be associated with disease progression of RA. Here, we observed the effect of SIN on MyD88 expression and showed its therapeutic role in RA. First, immunohistochemical staining in clinical specimens showed that MyD88 was mainly located in characteristic pathological structures of RA synovial tissues. Second, we found that MyD88 was overexpressed in the synovial tissues of the rats with adjuvant-induced arthritis (AIA). Treatment with SIN markedly decreased the expression of MyD88 in AIA rats. Finally, we provided evidences that SIN suppressed inflammation response and inflammation-induced joint destructive progression and arthritis symptoms in AIA rats. Therefore, SIN is an effective therapeutic agent for RA. Targeting MyD88 signaling may provide new methods for the treatment of RA.

  9. Intrathecal Midazolam as an Adjuvant in Pregnancy-Induced Hypertensive Patients Undergoing an Elective Caesarean Section: A Clinical Comparative Study

    PubMed Central

    Dodawad, Ravichandra; G. B., Sumalatha; Pandarpurkar, Sandeep; Jajee, Parashuram

    2016-01-01

    Background A pain-free postoperative period is essential following a caesarean section so new mothers may care for and bond with their neonates. Intrathecal adjuvants are often administered during this procedure to provide significant analgesia, but they may also have bothersome side effects. Intrathecal midazolam produces effective postoperative analgesia with no significant side effects. Objectives This prospective, randomized, double-blind study was designed to compare the analgesic efficacy and safety of intrathecal midazolam vs. plain bupivacaine as an adjunct to bupivacaine in pregnancy-induced hypertension patients scheduled for elective caesarean section. Methods Sixty patients diagnosed with pregnancy-induced hypertension on regular treatment who were scheduled for a caesarean section were randomly allocated into two groups: a control group (Group BC, n = 30) and a midazolam group (Group BM, n = 30). Both groups received 10 mg (2 mL) of 0.5% hyperbaric bupivacaine. Group BC received 0.4 mL of distilled water, while group BM received 0.4 mL (2 mg) of midazolam intrathecally. The duration of postoperative analgesia, analgesic requirements during the first 24 hours after surgery, onset times and durations of sensory and motor blocks, incidence of hypotension, vasopressor requirements, and side effects were recorded. Results Postoperative analgesia was significantly longer in the midazolam group compared to the control group (201.5 minutes vs. 357.6 minutes). The mean onset times of the sensory and motor blocks were significantly faster (P < 0.01) in the midazolam group compared to the control group. The mean times to attain the maximum sensory level and motor blocks were also significantly faster in the midazolam group compared to the control group (P < 0.05). The incidence of hypotension was 6.6% in the midazolam group and 36.6% in the control group, which was highly significant. In addition, the number of patients with side effects was significantly lower

  10. ER stress, p66shc, and p-Akt/Akt mediate adjuvant-induced inflammation, which is blunted by argirein, a supermolecule and rhein in rats.

    PubMed

    Cong, Xiao-Dong; Ding, Ming-Jian; Dai, De-Zai; Wu, You; Zhang, Yun; Dai, Yin

    2012-06-01

    We investigated the anti-inflammatory activities of argirein and rhein on inflammatory edema in rat paw which was caused by complete adjuvant, compared with ibuprofen. We hypothesized that the adjuvant-induced inflammation is attributed to upregulation of activating transcript factor 6 (ATF6; a chaperone for endoplasmic reticulum (ER) stress), p66Shc (an adaptive protein modulating oxidative stress), and NADPH oxidase subunits p22phox and gp91phox in the inflamed tissues. Biomarkers were measured in the rat paw in association with monitoring swellings. The primary inflammatory edema of the injected paw occurred rapidly and sustained over a couple of days, and the secondary inflammation developed 2 weeks later. The inflammatory edema was accompanied by upregulation of cytokines including ATF6, p66Shc, p22phox, gp91phox, and MMP-2 and an increase in ratio of p-Akt/Akt in the afflicted paw. These were suppressed by either argirein and rhein or ibuprofen. These findings indicate that ER stress, upregulated p66Shc, and phosphorylated Akt are actively implicated in the inflammatory zone caused by adjuvant injection. These biomarkers were causal factors responsible for inflammation of the afflicted paw and were suppressed by a supermolecule argirein and rhein, and the anti-inflammatory activities of the two compounds were comparable to that of ibuprofen.

  11. Candidate multi-epitope vaccines in aluminium adjuvant induce high levels of antibodies with predefined multi-epitope specificity against HIV-1.

    PubMed

    Ding, J; Lu, Y; Chen, Y

    2000-10-01

    Some neutralizing epitopes on HIV-1 envelope proteins were identified to induce antibodies which could effectively inhibit the infection of different strains in vitro. But only very low levels of these antibodies were determined in the HIV-1 infected individuals. To increase the levels of protective antibodies in vivo, we suggested multi-epitope vaccine as a new strategy to induce high level of neutralization antibodies with predefined multi-epitope specificity. A synthesized epitope peptide MP (CG-GPGRAFY-G-ELDKWA-G-RILAVERYLKD) containing three neutralizing epitopes (GPGRAFY, ELDKWA, RILAVERYLKD) was conjugated to carrier protein KLH, and then used for immunization in mouse together with aluminium adjuvant or Freund's adjuvant (FA). The candidate MP-KLH multi-epitope vaccine in aluminium adjuvant could induce antibody response very strongly to the epitope peptide C-(RILAVERYLKD-G)2 and the immunosuppressive peptide (P1) (LQARILAVERYLKDQQL) (antibody titer: 1:51200), strongly to the epitope peptide C-(ELDKWA-G)4 and the C-domain peptide (P2) (1:12800), and moderately to the epitope peptide C-(GPGRAFY)4 and the V3 loop peptide (1:1600). The immunoblotting analysis demonstrated that the antibodies in sera could recognize P1, P2, V3 loop peptides and rsgp41 (aa 539-684). These results are similar with that in the case of PI-BSA in FA, and suggest that the multi-epitope vaccine in aluminium could induce high levels of antibodies of predefined multi-epitope specificity, which provides experimental evidence for the new strategy to develop an effective neutralizing antibody-based multi-epitope vaccine against HIV-1.

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

    PubMed

    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.

  13. Self-adjuvanting C18 lipid vinil sulfone-PP2A vaccine: study of the induced immunomodulation against Trichuris muris infection.

    PubMed

    Gomez-Samblas, M; García-Rodríguez, J J; Trelis, M; Bernal, D; Lopez-Jaramillo, F J; Santoyo-Gonzalez, F; Vilchez, S; Espino, A M; Bolás-Fernández, F; Osuna, A

    2017-04-01

    Despite the importance of the adjuvant in the immunization process, very few adjuvants merge with the antigens in vaccines. A synthetic self-adjuvant oleic-vinyl sulfone (OVS) linked to the catalytic region of recombinant serine/threonine phosphatase 2A from the nematode Angiostrongylus costaricensis (rPP2A) was used for intranasal immunization in mice previously infected with Trichuris muris The animal intranasal immunization with rPP2A-OVS showed a reduction of 99.01% in the number of the nematode eggs and 97.90% in adult. The immunohistochemical analysis of the intestinal sections showed that in immunized animals with lipopeptide the mucus was significantly higher than in the other experimental groups. Also, these animals presented significantly different chemokine, CCL20 and CCL11, levels. However, although the number and size of Tuft cells did not vary between groups, the intensity of fluorescence per cell was significant in the group immunized with the rPP2A-OVS. The results of the present study suggest that mice immunized with the lipopeptide are capable of activating a combined Th17/Th9 response. This strategy of immunization may be of great applicability not only in immunotherapy and immunoprophylaxis to control diseases caused by nematodes but also in pathologies necessitating action at the level of the Th9 response in the intestinal mucosa.

  14. Self-adjuvanting C18 lipid vinil sulfone-PP2A vaccine: study of the induced immunomodulation against Trichuris muris infection

    PubMed Central

    Gomez-Samblas, M.; García-Rodríguez, J. J.; Trelis, M.; Bernal, D.; Lopez-Jaramillo, F. J.; Santoyo-Gonzalez, F.; Vilchez, S.; Espino, A. M.; Bolás-Fernández, F.

    2017-01-01

    Despite the importance of the adjuvant in the immunization process, very few adjuvants merge with the antigens in vaccines. A synthetic self-adjuvant oleic-vinyl sulfone (OVS) linked to the catalytic region of recombinant serine/threonine phosphatase 2A from the nematode Angiostrongylus costaricensis (rPP2A) was used for intranasal immunization in mice previously infected with Trichuris muris. The animal intranasal immunization with rPP2A-OVS showed a reduction of 99.01% in the number of the nematode eggs and 97.90% in adult. The immunohistochemical analysis of the intestinal sections showed that in immunized animals with lipopeptide the mucus was significantly higher than in the other experimental groups. Also, these animals presented significantly different chemokine, CCL20 and CCL11, levels. However, although the number and size of Tuft cells did not vary between groups, the intensity of fluorescence per cell was significant in the group immunized with the rPP2A-OVS. The results of the present study suggest that mice immunized with the lipopeptide are capable of activating a combined Th17/Th9 response. This strategy of immunization may be of great applicability not only in immunotherapy and immunoprophylaxis to control diseases caused by nematodes but also in pathologies necessitating action at the level of the Th9 response in the intestinal mucosa. PMID:28404797

  15. Peptide vaccination in Montanide adjuvant induces and GM-CSF increases CXCR3 and cutaneous lymphocyte antigen expression by tumor antigen-specific CD8 T cells.

    PubMed

    Clancy-Thompson, Eleanor; King, Laura K; Nunnley, Lenora D; Mullins, Irene M; Slingluff, Craig L; Mullins, David W

    2013-11-01

    T cell infiltration of melanoma is associated with enhanced clinical efficacy and is a desirable endpoint of immunotherapeutic vaccination. Infiltration is regulated, in part, by chemokine receptors and selectin ligands on the surface of tumor-specific lymphocytes. Therefore, we investigated the expression of two homing molecules--CXCR3 and CLA - on vaccine-induced CD8 T cells, in the context of a clinical trial of a melanoma-specific peptide vaccine. Both CXCR3 and CLA have been associated with T cell infiltration of melanoma. We demonstrate that a single subcutaneous/intradermal administration of peptide vaccine in Montanide adjuvant induces tumor-specific CD8 T cells that are predominantly positive for CXCR3, with a subpopulation of CXCR3(+)CLA(+) cells. Addition of GM-CSF significantly enhances CXCR3 expression and increases the proportion of CLA-expressing cells. Concurrent with CXCR3 and CLA expression, vaccine-induced CD8 cells express high levels of Tbet, IFN-γ, and IL-12Rβ1. Collectively, these studies demonstrate that peptide vaccination in adjuvant induces CD8 T cells with a phenotype that may support infiltration of melanoma.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  18. Attenuation of hemorrhage-associated lung injury by adjuvant treatment with C23, an oligopeptide derived from cold-inducible RNA-binding protein.

    PubMed

    Zhang, Fangming; Yang, Weng-Lang; Brenner, Max; Wang, Ping

    2017-10-01

    Hemorrhagic shock (HS) is an important cause of mortality. HS is associated with an elevated incidence of acute lung injury and acute respiratory distress syndrome, significantly contributing to HS morbidity and mortality. Cold-inducible RNA-binding protein (CIRP) is released into the circulation during HS and can cause lung injury. C23 is a CIRP-derived oligopeptide that binds with high affinity to the CIRP receptor and inhibits CIRP-induced phagocyte secretion of TNF-α. This study was designed to determine whether C23 is able to attenuate HS-associated lung injury. C57BL/6 mice were subjected to controlled hemorrhage leading to a mean arterial pressure of 25 ± 3 mm Hg for 90 minutes. Mice were then volume-resuscitated for 30 minutes with normal saline solution alone (vehicle) or plus adjuvant treatment with C23 (8 mg/kg BW). At 4.5 hours after resuscitation, the blood and lungs were harvested. Serum levels of organ injury markers lactate dehydrogenase, aspartate aminotransferase were significantly elevated in hemorrhaged mice receiving vehicle and were reduced by 51.3% and 52.2% in mice adjuvantly treated with C23, respectively. Similarly, lung mRNA levels of IL-1β, TNF-α, and IL-6, and lung myeloperoxidase activity were elevated after HS and reduced by 66.1%, 54.4%, 69.7%, and 24.3%, respectively, in mice treated with C23. Adjuvant treatment with C23 also decreased the lung histology score by 33.9%, lung extravasation of albumin carrying Evans blue dye by 36.8%, and the protein level of intercellular adhesion molecule-1, and indicator of vascular endothelial cell activation, by 40.3%. Together, these results indicate that adjuvant treatment with the CIRP-derived oligopeptide C23 is able to improve lung inflammation and vascular endothelial activation secondary to HS, lending support to the development of CIRP-targeting adjuvant treatments to minimize lung injury after HS.

  19. AS03-adjuvanted H7N1 detergent-split virion vaccine is highly immunogenic in unprimed mice and induces cross-reactive antibodies to emerged H7N9 and additional H7 subtypes.

    PubMed

    Mallett, Corey P; Beaulieu, Edith; Joly, Marie-Hélène; Baras, Benoît; Lu, Xiuhua; Liu, Feng; Levine, Min Z; Katz, Jacqueline M; Innis, Bruce L; Giannini, Sandra L

    2015-07-31

    Avian H7 is one of several influenza A virus subtypes that have the potential to cause pandemics. Herein we describe preclinical results following administration of an investigational H7N1 inactivated detergent-split virion vaccine adjuvanted with the AS03 Adjuvant System. The adjuvanted H7N1 vaccine was highly immunogenic compared to the non-adjuvanted H7N1 vaccine in unprimed mice with less than 100ng of hemagglutinin antigen per dose. In addition, compared to the non-adjuvanted vaccine, the AS03-adjuvanted H7N1 vaccine also induced robust HI and VN antibody responses that cross-reacted with other H7 subtypes, including recently emerged H7N9 virus. These H7 data from the preclinical mouse model add to the existing H5 data to suggest that AS03 adjuvant technology may be generally effective for formulating antigen-sparing detergent-split virion vaccines against intrinsically sub-immunogenic avian influenza A virus subtypes. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. In vivo antiarthritic activity of the ethanol extracts of stem bark and seeds of Calophyllum inophyllum in Freund's complete adjuvant induced arthritis.

    PubMed

    Perumal, Senthamil Selvan; Ekambaram, Sanmuga Priya; Dhanam, T

    2017-12-01

    Calophyllum inophyllum Linn. (Clusiaceae) (CI) is traditionally used to treat pain, inflammation, eye disorders and rheumatism. The present study evaluates the antiarthritic activity of the ethanol extract of the stem bark (ESBCI) and seeds (ESCI) of Calophyllum inophyllum in Freund's adjuvant induced arthritic Wistar albino rat model. ESBCI and ESCI were screened for in vitro anti-inflammatory activity by proteinase inhibition and membrane stabilization assays. Acute oral toxicity studies were conducted according to OECD-425 guidelines. Antiarthritic activity of ESBCI and ESCI at the dose of 250 mg/kg/p.o. was evaluated by Freund's adjuvant induced arthritic rat model. ESBCI and ESCI have shown maximum inhibition at 250 μg/mL in proteinase inhibition and haemolysis assays. The LD50 of ESBCI and ESCI was found to be greater than 5000 and 2000 mg/kg/p.o., respectively. In Freund's adjuvant induced arthritic rat model ESBCI, ESCI and Diclofenac treatment have shown 28.57, 36.36, and 43.51% as maximum reduction in rat paw oedema volume respectively when compared with the arthritic control rats. ESBCI and ESCI treatment at the dose level of 250 mg/kg/p.o. normalized the altered haematological and biochemical parameters of arthritic control rats. Histological and radiological evaluation confirmed the antiarthritic effect of ESBCI and ESCI. ESBCI and ESCI were found to show significant antiarthritic activity evidenced with clinical, biochemical, histological and radiological evaluations. The present study indicates the antiarthritic activity of ESBCI and ESCI, however its mechanism of action has to be studied in the future.

  1. 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.

    PubMed

    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

    2017-02-22

    Several prophylactic vaccines targeting HSV-2 have failed in the clinic to demonstrate a sustained depression in viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies, 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 neutralizing antibody (nAb) targets gD and gB, the novel T cell antigen and tegument protein UL40, and we compared this to a whole-inactivated virus vaccine (FI-HSV-2). We evaluated different formulations in combination with several Th1-inducing TLR agonists in vivo. In mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted the most robust, functional HSV-2 antigen-specific CD8 T cell responses and high neutralizing antibodies, demonstrating 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 type 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors of clinical trials. Attempts to develop a vaccine have focused primarily on

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

    PubMed

    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

  3. Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvant-induced arthritis primarily through blockade of ROS formation, NFkB and MAPK activation.

    PubMed

    Hsu, Chun-Chieh; Lien, Jin-Cherng; Chang, Chia-Wen; Chang, Chien-Hsin; Kuo, Sheng-Chu; Huang, Tur-Fu

    2013-02-01

    Phagocytes release inflammatory mediators to defense harmful stimuli upon bacterial invasion, however, excessive inflammatory reaction leads to tissue damage and manifestation of pathological states. Therefore, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-associated diseases. Under the drug screening process of synthetic diphenylpyrazole derivatives, we discovered compound yuwen02f1 possesses anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNFα and IL-6, nitric oxide, reactive oxygen species (ROS) as well as inhibiting migration of LPS-stimulated phagocytes. In addition, we observed that the molecular mechanism of yuwen02f1-mediated anti-inflammation is associated with decreasing phosphorylation of MAPK molecules including ERK1/2, JNK and p38, and attenuating translocation of p47(phox) and p67(phox) to the cell membrane. Yuwen02f1 also reverses IκBα degradation and attenuates the expression of NFκB-related downstream inducible enzymes like iNOS and COX-2. Furthermore, we found that yuwen02f1 attenuates some pathological syndromes of LPS-induced sepsis and adjuvant-induced arthritis in mice, as evidenced by decreasing the cytokine production, reversing thrombocytopenic syndrome, protecting the mice from tissue injury in septic mice, and attenuating paw edema in arthritic mice as well. These results suggest that yuwen02f1 is a potential anti-inflammatory agent for alleviating syndromes of acute and chronic inflammatory diseases as evidenced by attenuating the generation of cytokines and down-regulating the expression of iNOS and COX-2 through the blockade of ROS generation and NADPH oxidase, NFκB and MAPK activation pathways in LPS-stimulated phagocytes. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2016-06-01

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

  6. Stimulation of IgY responses in gene gun immunized laying hens by combined administration of vector DNA coding for the target antigen Botulinum toxin A1 and for avian cytokine adjuvants.

    PubMed

    Niederstadt, Lars; Hohn, Oliver; Dorner, Brigitte G; Schade, Rüdiger; Bannert, Norbert

    2012-08-31

    DNA immunization is a convenient and effective way of inducing a specific antibody response. In mammals, co-administration of vectors encoding immunostimulatory cytokines can enhance the humoral response resulting in elevated antibody titers. We therefore set out to investigate the effect using avian interleukin 1β (IL-1β) and avian interleukin 6 (IL-6) as genetic adjuvants when immunizing laying hens. A BoNT A1 holotoxoid DNA immunogen carrying two inactivating mutations was evaluated for its ability to induce a specific and sustained IgY antibody response. Both the holotoxoid and the cytokine sequences were codon-optimized. In vitro, the proteins were efficiently expressed in transfected HEK 293T cells and the cytokines were secreted into the culture supernatants. Whereas eggs from hens immunized via gene gun using a prime boost strategy showed no differences in their total IgY content, the specific αBoNT A1 response was slightly elevated up to 1.4× by the IL-1β adjuvant vector and increased by 3.8× by the IL-6 vector. Finally, although hens receiving the IL-1β adjuvant had laying capacities above the average, hens receiving the IL-6 adjuvant experienced laying problems.

  7. Alum induces innate immune responses through macrophage and mast cell sensors, but these are not required for alum to act as an adjuvant for specific immunity.12

    PubMed Central

    McKee, Amy S.; Munks, Michael W.; MacLeod, Megan K. L.; Fleenor, Courtney J.; Van Rooijen, Nico; Kappler, John W.; Marrack, Philippa

    2010-01-01

    To understand more about how the body recognizes alum we characterized the early innate and adaptive responses in mice injected with the adjuvant. Within hours of exposure, alum induces a type 2 innate response characterized by an influx of eosinophils, monocytes, neutrophils, DCs, NK cells and NKT cells. In addition, at least thirteen cytokines and chemokines are produced within 4 hours of injection including IL-1β and IL-5. Optimal production of some of these, including IL-1β, depends upon both macrophages and mast cells, while production of others, such as IL-5, depends on mast cells only, suggesting that both of these cell types can detect alum. Alum induces eosinophil accumulation partly through the production of mast cell derived IL-5 and histamine. Alum greatly enhances priming of endogenous CD4 and CD8 T cells independently of mast cells, macrophages and of eosinophils. In addition, antibody levels and Th2 bias was similar in the absence of these cells. We found that the inflammation induced by alum was unchanged in caspase-1 deficient mice, which cannot produce IL-1β. Furthermore, endogenous CD4 and CD8 T cell responses, antibody responses and the Th2 bias were also not impacted by the absence of caspase-1 or NLRP3. These data suggest that activation of the inflammasome and the type 2 innate response orchestrated by macrophages and mast cells in vivo are not required for alum's adjuvant effects on endogenous T and B cell responses. PMID:19734227

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

    PubMed Central

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

    2016-01-01

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

  9. Novel adjuvant therapies for pancreatic adenocarcinoma

    PubMed Central

    Oyasiji, Tolutope

    2015-01-01

    Contemporary adjuvant therapy for pancreatic cancer patients following surgical resection includes chemotherapy and chemoradiotherapy. However, the median survival remains approximately 20 months despite multi-modality treatment using gemcitabine or fluoropyrimidine systemic chemotherapy. Adjuvant randomized trials are currently underway to evaluate cytotoxic combinations found to be active in advanced disease including FOLFIRINOX, gemcitabine/nab-paclitaxel and gemcitabine/capecitabine. Immunotherapy using genetically engineered cell-based vaccines had shown promise in resected pancreatic cancer patients during early phase trials, and algenpantucel-L vaccine is currently being evaluated in adjuvant setting in a randomized trial. This review focuses on novel adjuvant therapies currently in clinical evaluation. PMID:26261729

  10. Squalene-adjuvanted H7N9 virus vaccine induces robust humoral immune response against H7N9 and H7N7 viruses.

    PubMed

    Wu, Chia-Ying; Chang, Ching-Yuan; Ma, Hsiu-Hua; Wang, Chiung-Wen; Chen, Yung-Tsung; Hsiao, Pei-Wen; Chang, Ching-Chuan; Chan, Chi-Hsien; Liu, Chung-Cheng; Chen, Juine-Ruey

    2014-07-31

    Recent cases of avian influenza H7N9 have caused great concerns that virus may become transmittable between humans. It is imperative to develop an effective vaccine to fight against the pandemic potential of this H7N9 influenza virus to protect human from the disease. This study aims to investigate an optimized formulation for the development of H7N9 vaccines. Various doses of H7N9 inactivated whole or split-virus antigens (0.5, 1.5, or 3 μg based on hemagglutinin content) combined with squalene-based adjuvant (AddaVAX), aluminum hydroxide Al(OH)3 or without adjuvant were evaluated for the efficacy of H7N9 vaccine regiments in mice. With either H7N9 whole or split-virus based vaccines, AddaVAX-adjuvanted formulations were the most immunogenic in eliciting significant humoral immune response against H7N9 virus and exhibited strong cross-reactive response in hemagglutination inhibition (HAI) and viral-neutralization assays against H7N7 virus as well. In contrast, formulations with Al(OH)3 or without adjuvant were less immunogenic and elicited lower titers of HAI and microneutralization assays against both viruses. Dose-sparing experiments suggested that the formulation with as low as 0.004 μg of split or whole virus vaccine antigens together with 50% AddaVAX provided sufficient sero-protective HAI titers and achieved essential virus-neutralizing antibody titers against H7-subtype influenza viruses in mice. Protection experiments demonstrated that the formulation of 0.004 μg to 0.5 μg of split-virion vaccines with AddaVAX conferred full protection against viral challenge up to 100 LD50 of wild-type H7N9 virus, with 0% survival in placebo group. Taken together, our study demonstrates that squalene-based adjuvant can significantly enhance the protective efficacy of H7N9 virus vaccine and provides a useful strategy to confront the potential pandemic outbreaks of H7N9 virus. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    PubMed Central

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

    2014-01-01

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

  12. Feasibility and effects of a combined adjuvant high-intensity interval/strength training in breast cancer patients: a single-center pilot study.

    PubMed

    Schulz, Sebastian Viktor Waldemar; Laszlo, Roman; Otto, Stephanie; Prokopchuk, Dmytro; Schumann, Uwe; Ebner, Florian; Huober, Jens; Steinacker, Jürgen Michael

    2017-03-21

    To evaluate feasibility of an exercise intervention consisting of high-intensity interval endurance and strength training in breast cancer patients. Twenty-six women with nonmetastatic breast cancer were consecutively assigned to the exercise intervention- (n= 15, mean age 51.9 ± 9.8 years) and the control group (n = 11, mean age 56.9 ± 7.0 years). Cardiopulmonary exercise testing that included lactate sampling, one-repetition maximum tests and a HADS-D questionnaire were used to monitor patients both before and after a supervised six weeks period of either combined high-intensity interval endurance and strength training (intervention group, twice a week) or leisure training (control group). Contrarily to the control group, endurance (mean change of VO2, peak 12.0 ± 13.0%) and strength performance (mean change of cumulative load 25.9 ± 11.2%) and quality of life increased in the intervention group. No training-related adverse events were observed. Our guided exercise intervention could be used effectively for initiation and improvement of performance capacity and quality of life in breast cancer patients in a relatively short time. This might be especially attractive during medical treatment. Long-term effects have to be evaluated in randomized controlled studies also with a longer follow-up. Implications for Rehabilitation High-intensity interval training allows improvement of aerobic capacity within a comparable short time. Standard leisure training in breast cancer patients is rather suitable for the maintenance of performance capacity and quality of life. Guided high-intensity interval training combined with strength training can be used effectively for the improvement of endurance and strength capacity and also quality of life. After exclusion of contraindications, guided adjuvant high-intensity interval training combined with strength training can be safely used in breast cancer patients.

  13. Effect of Andrographis paniculata as an adjuvant in combined chemo-radio and whole body hyperthermia treatment - a preliminary study.

    PubMed

    Sheeja, K; Kuttan, G

    2008-01-01

    Modulation of immune responses to alleviate disease has been of interest for a long time. Intraperitoneal administration of Andrographis paniculata extract along with whole body hyperthermia (WBH) was found to enhance the total WBC count in cyclophosphamide (CTX) and radiation treated animals when compared to untreated control animals. Maximum inhibition in the solid tumor development was observed when the CTX and radiation exposed animals were treated with extract in combination with whole-body hyperthermia. Similarly myeloperoxidase activity in tumor tissue from CTX and radiation-treated animals was also significantly inhibited when they were administered with Andrographis paniculata extract along with whole body hyperthermia. Moreover the production of cytokines such as IL-2 and GM-CSF, which was reduced after combined CTX and radiation treatment was significantly increased by the simultaneous treatment of extract and whole body hyperthermia. The elevated level of serum Tumor Necrosis Factor (TNF-alpha) level, after CTX and radiation treatment was also lowered significantly after the administration of extract and simultaneous exposure of whole-body hyperthermia with respect to untreated tumor-bearing animals.

  14. Comparative efficacy of ropivacaine and levobupivacaine in combined femoral and lateral femoral cutaneous nerve block with adjuvant magnesium for post-operative analgesia

    PubMed Central

    Khairnar, Prakash; Agarwal, Munisha; Verma, Uttam Chandra; Kumar, Rakesh

    2016-01-01

    Background and Aims: Patients with burns may require multiple surgeries, but poor general condition and underlying protein energy malnutrition make them unsuitable candidates for general or spinal anaesthesia. This study evaluated the role of magnesium sulphate as an adjuvant with levobupivacaine and ropivacaine used in combined femoral and lateral femoral cutaneous nerve (LFCN) blocks in burn patients with relative sparing of thigh portion. Methods: This prospective, randomised, double-blind study included 54 adult patients of 18–65 years age, undergoing split-thickness skin graft harvest from the thigh, allotted to three equal groups of 18 each. Group L patients received femoral nerve (FN) block with 15 mL of 0.5% levobupivacaine and 8 mL for LFCN block; Group LM patients received 14 mL of 0.5% levobupivacaine along with 1.0 mL of 15% magnesium sulphate for FN block, 7.5 mL of 0.5% levobupivacaine with 0.5 mL of 15% of magnesium sulphate to LFCN block and Group R patients received 15 mL of 0.5% ropivacaine for FN block and 8 mL of 0.5% ropivacaine for LFCN block. Time to block onset and complete surgical block, duration of analgesia, total analgesic dose and the overall analgesia satisfaction score were measured in the first 24 h post-operatively. Quantitative data were analysed with ANOVA and qualitative data subjected to Chi-square tests. Intergroup comparison was performed with independent t-test. Results: The duration of post-operative analgesia did not differ with the addition of magnesium (P = 0.610). Time to onset of the block was significantly decreased with the addition of magnesium (P = 0.0341), but time to complete surgical block onset was similar across the groups. Conclusion: Both ropivacaine and levobupivacaine have good perioperative analgesic efficacy. Magnesium as an analgesia adjuvant with levobupivacaine does not prolong the duration of post-operative analgesia. PMID:27601742

  15. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis.

    PubMed

    Wang, Haiqing; Liu, Aixiang; Bo, Wentao; Feng, Xielin; Hu, Yong; Tian, Lang; Zhang, Hui; Tang, Xiaoli

    2016-11-01

    Cytokine-induced killer cells have been used as an adjuvant treatment for hepatocellular carcinoma with curative treatment. However, the outcomes remain controversial. We conducted this meta-analysis to assess the safety and efficacy of cytokine-induced killer cells. Randomized controlled trials on cytokine-induced killer cells for hepatocellular carcinoma after curative treatments were identified by electronic searches. A meta-analysis was carried out to examine disease-free survival, overall survival rate and adverse effect. Six randomized controlled trials with 844 patients (85.9% with hepatitis B or C) were included. Our meta-analysis showed that cytokine-induced killer cells can not only improve the 1-year (RR=1.23, P<0.001), 2-year (RR=1.37, P<0.001) and 3-year (RR=1.35, P=0.004) disease-free survival, but also improve the 1-year (RR=1.08, P=0.001), 2-year (RR=1.14, P<0.001) and 3-year (RR=1.15, P=0.02) overall survival. However, it failed to affect the 4-year and 5-year disease-free survival and overall survival (P>0.05). At the same time, cytokine-induced killer cells treatment was proved to be a safe strategy with the comparable adverse events comparing to the control group (P=0.39). This review provides the best available evidence that adjuvant cytokine-induced killer cells treatment can be safely used to improve the early disease-free survival and survival of hepatitis B or C related hepatocellular carcinoma. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  16. A novel vaccinological evaluation of intranasal vaccine and adjuvant safety for preclinical tests.

    PubMed

    Sasaki, Eita; Kuramitsu, Madoka; Momose, Haruka; Kobiyama, Kouji; Aoshi, Taiki; Yamada, Hiroshi; Ishii, Ken J; Mizukami, Takuo; Hamaguchi, Isao

    2017-02-01

    Vaccines are administered to healthy humans, including infants, so the safety and efficacy must be very high. Therefore, evaluating vaccine safety in preclinical and clinical studies, according to World Health Organization guidelines, is crucial for vaccine development and clinical use. A change in the route of administration is considered to alter a vaccine's immunogenicity. Several adjuvants have also been developed and approved for use in vaccines. However, the addition of adjuvants to vaccines may cause unwanted immune responses, including facial nerve paralysis and narcolepsy. Therefore, a more accurate and comprehensive strategy must be used to develope next-generation vaccines for ensuring vaccine safety. Previously, we have developed a system with which to evaluate vaccine safety in rats using a systematic vaccinological approach and 20 marker genes. In this study, we developed a safety evaluation system for nasally administered influenza vaccines and adjuvanted influenza vaccines using these marker genes. Expression of these genes increased dose-dependent manner when mice were intranasally administered the toxicity reference vaccine. When the adjuvant CpG K3 or a CpG-K3-combined influenza vaccine was administered intranasally, marker gene expression increased in a CpG-K3-dose-dependent way. A histopathological analysis indicated that marker gene expression correlated with vaccine- or adjuvant-induced phenotypic changes in the lung and nasal mucosa. We believe that the marker genes expression analyses will be useful in preclinical testing, adjuvant development, and selecting the appropriate dose of adjuvant in nasal administration vaccines.

  17. Effects of diquat and fomesafen applied alone and in combination with a nonylphenol polyethoxylate adjuvant on Lemna minor in aquatic indoor microcosms.

    PubMed

    Gorzerino, Caroline; Quemeneur, Alphonse; Hillenweck, Anne; Baradat, Maryse; Delous, Georges; Ollitrault, Martine; Azam, Didier; Caquet, Thierry; Lagadic, Laurent

    2009-03-01

    The influence of tank-mix adjuvants on pesticide toxicity remains largely unknown. Agral 90, a nonylphenol polyethoxylated tank-mix adjuvant, has been used with diquat (bipyridylium herbicide) and fomesafen (diphenyl-ether herbicide) in aquatic indoor microcosms in order to compare the toxicity of the single compounds and of binary herbicide-adjuvant mixtures to Lemna minor. Twenty-four microcosms were used and treatments were performed with substances alone or with herbicide-adjuvant binary mixtures, at two concentrations levels (44.4 and 222.2 microg/L for the herbicides, and 100 and 500 microg/L for Agral 90). Toxicity was assessed weekly for 1 month through growth measurements, as inferred from the relative frond number (RFN) and relative frond area (RFA). Concentrations of diquat and fomesafen in water and sediments were measured weekly. The herbicides showed very different behaviour in microcosms, with a rapid disappearance of diquat from the aqueous phase whereas fomesafen levels remained almost constant over time. Diquat strongly inhibited the growth of L. minor whereas fomesafen had no effect on plant growth. Presence of the adjuvant only slightly reduced the effect of the lowest concentration of diquat, probably as a result of dispersion of the herbicide at the water surface. It is concluded that tank-mix adjuvant designed to improve herbicide efficiency in the terrestrial environment did not have any effect on aquatic plants when applied to the aquatic environment.

  18. Broad Clade 2 Cross-Reactive Immunity Induced by an Adjuvanted Clade 1 rH5N1 Pandemic Influenza Vaccine

    PubMed Central

    Leroux-Roels, Isabel; Bernhard, Roger; Gérard, Pascal; Dramé, Mamadou; Hanon, Emmanuel; Leroux-Roels, Geert

    2008-01-01

    Background The availability of H5N1 vaccines that can elicit a broad cross-protective immunity against different currently circulating clade 2 H5N1 viruses is a pre-requisite for the development of a successful pre-pandemic vaccination strategy. In this regard, it has recently been shown that adjuvantation of a recombinant clade 1 H5N1 inactivated split-virion vaccine with an oil-in-water emulsion-based adjuvant system also promoted cross-immunity against a recent clade 2 H5N1 isolate (A/Indonesia/5/2005, subclade 2.1). Here we further analyse the cross-protective potential of the vaccine against two other recent clade 2 isolates (A/turkey/Turkey/1/2005 and A/Anhui/1/2005 which are, as defined by WHO, representatives of subclades 2.2 and 2.3 respectively). Methods and Findings Two doses of the recombinant A/Vietnam/1194/2004 (H5N1, clade 1) vaccine were administered 21 days apart to volunteers aged 18–60 years. We studied the cross-clade immunogenicity of the lowest antigen dose (3.8 µg haemagglutinin) given with (N = 20) or without adjuvant (N = 20). Immune responses were assessed at 21 days following the first and second vaccine doses and at 6 months following first vaccination. Vaccination with two doses of 3.8 µg of the adjuvanted vaccine induced four-fold neutralising seroconversion rates in 85% of subjects against A/turkey/Turkey/1/2005 (subclade 2.2) and 75% of subjects against A/Anhui/1/2005 (subclade 2.3) recombinant strains. There was no response induced against these strains in the non-adjuvanted group. At 6 months following vaccination, 70% and 60% of subjects retained neutralising antibodies against the recombinant subclade 2.2 and 2.3 strains, respectively and 40% of subjects retained antibodies against the recombinant subclade 2.1 A/Indonesia/5/2005 strain. Conclusions In addition to antigen dose-sparing, adjuvantation of inactivated split H5N1 vaccine promotes broad and persistent cross-clade immunity which is a pre-requisite for a pre

  19. Anti-bone resorption activity of deer antler aqua-acupunture, the pilose antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe (Nokyong) in adjuvant-induced arthritic rats.

    PubMed

    Kim, Kyung-Ho; Kim, Kap-Sung; Choi, Byeong-Joon; Chung, Kang-Hyun; Chang, Young-Chae; Lee, Seung-Duk; Park, Kwan-Kyu; Kim, Hyung-Min; Kim, Cheorl-Ho

    2005-01-15

    Effect of deer antler aqua-acupunture (DAA), prepared from the pilose antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe, a traditional immunosuppressive acupuncture, was evaluated to assess the reductions in bone mass, strength, and turnover in adjuvant-induced arthritic rats. For measuring the above parameters, a 20-day dosing experiment was performed using 6-week-old female Lewis rats. Arthritis was induced by injecting the adjuvant into the hind paw of the Lewis rats. The age-dependent increases in the body weight, lumbar bone mineral content and density (BMC and BMD) and compressive strength were disturbed in the arthritic rats. At 10 days, the histomorphometric parameters of bone formation (BFR/BS and BFR/BV) and the serum osteocalcin levels were significantly reduced compared with the baseline controls of Lewis rats. However, the BMC values corrected for body weight did not differ significantly between the arthritic and normal rats, and the bone minerals were not reduced when they were compared with the baseline controls. At 20 days, the parameters of bone minerals and strength of the lumbar body in the arthritic rats, both with and without correction for body weight, were significantly reduced compared with the baseline controls. The trabecular mineralizing surface remained significantly reduced and the osteoclast numbers were increased. DAA at the doses of 10, 20, 50 and 100 microg/kg, administered by Shinsu (B23) acupuncture daily from the start of the experiment, significantly prevented the development of the chronic paw edema at 20 days. The reductions in the parameters such as bone minerals, strength, and trabecular bone formation, and the increase in osteoclast number were alleviated by this DAA. Age-dependent increases in the lumbar height, disturbed by the adjuvant injection, were also maintained. These results indicated that a 20-day-period is necessary to obtain sufficient reductions in the bone mass and strength of the lumbar body

  20. Long-Term Treatment by Vitamin B1 and Reduction of Serum Proinflammatory Cytokines, Hyperalgesia, and Paw Edema in Adjuvant-Induced Arthritis

    PubMed Central

    Zaringhalam, Jalal; Akbari, Akhtar; Zali, Alireza; Manaheji, Homa; Nazemian, Vida; Shadnoush, Mahdi; Ezzatpanah, Somayeh

    2016-01-01

    Introduction: Immune system is involved in the etiology and pathophysiology of inflammation and vitamins are important sources of substances inducing nonspecific immunomodulatory effects. Given the proinflammatory role of cytokines in the inflammation and pain induction, this study aimed to assess the effects of long-term administration of vitamin B1 on the proinflammatory cytokines, edema, and hyperalgesia during the acute and chronic phases of adjuvant-induced arthritis. Methods: On the first day of study, inflammation was induced by intraplantar injection of complete Freund's adjuvant (CFA) in the hindpaws of rats. Vitamin B1 at doses of 100, 150, and 200 mg/kg was administrated intraperitoneally during 21 days of the study. Antinociceptive and anti-inflammatory effects of vitamin B1 were also compared to indomethacin (5 mg/kg). Inflammatory symptoms such as thermal hyperalgesia and paw edema were measured by radiant heat and plethysmometer, respectively. Serum TNF-α and IL-1β levels were checked by rat standard enzyme-linked immune sorbent assay (ELISA) specific kits. Results: The results indicated that vitamin B1(150 and 200 mg/kg) attenuated the paw edema, thermal hyperalgesia, and serum levels of TNF-α and IL-1β during both phases of CFA-induced inflammation in a dose-dependent manner. Effective dose of vitamin B1(150 mg/kg) reduced inflammatory symptoms and serum levels of TNF-α and IL-1β compare to indomethacin during the chronic phase of inflammation. Conclusion: Anti-inflammatory and antihyperalgesic effects of vitamin B1 during CFA-induced arthritis, more specifically after chronic vitamin B1 administration, suggest its therapeutic property for inflammation. PMID:27872694

  1. Bacillus subtilis spores as adjuvants for DNA vaccines.

    PubMed

    Aps, Luana R M M; Diniz, Mariana O; Porchia, Bruna F M M; Sales, Natiely S; Moreno, Ana Carolina R; Ferreira, Luís C S

    2015-05-11

    Recently, Bacillus subtilis spores were shown to be endowed with strong adjuvant capacity when co-administered with purified antigenic proteins. In the present study we assessed whether spores possess adjuvant properties when combined with DNA vaccines. We showed that B. subtilis spores promoted the activation of dendritic cells in vitro and induced migration of pro-inflammatory cells after parenteral administration to mice. Likewise, co-administration of spores with a DNA vaccine encoding the human papillomavirus type 16 (HPV-16) E7 protein enhanced the activation of antigen-specific CD8(+) T cell responses in vivo. Mice immunized with the DNA vaccine admixed with spores presented a protective immunity increase to previously implanted tumor cells, capable of expressing HPV-16 oncoproteins. Finally, we observed that the adjuvant effect can vary accordingly to the number of co-administered spores which may be ascribed with the ability to induce. Collectively, the present results demonstrate for the first time that B. subtilis spores can also confer adjuvant effects to DNA vaccines.

  2. A Fasciola hepatica-derived fatty acid binding protein induces protection against schistosomiasis caused by Schistosoma bovis using the adjuvant adaptation (ADAD) vaccination system.

    PubMed

    Vicente, Belén; López-Abán, Julio; Rojas-Caraballo, José; Pérez del Villar, Luis; Hillyer, George V; Martínez-Fernández, Antonio R; Muro, Antonio

    2014-10-01

    Several efforts have been made to identify anti-schistosomiasis vaccine candidates and new vaccination systems. The fatty acid binding protein (FAPB) has been shown to induce a high level of protection in trematode infection. The adjuvant adaptation (ADAD) vaccination system was used in this study, including recombinant FABP, a natural immunomodulator and saponins. Mice immunised with the ADAD system were able to up-regulate proinflammatory cytokines (IL-1 and IL-6) and induce high IgG2a levels. Moreover, there was a significant reduction in worm burden, egg liver and hepatic lesion in vaccinated mice in two independent experiments involving Schistosoma bovis infected mice. The foregoing data shows that ADAD system using FABP provide a good alternative for triggering an effective immune response against animal schistosomiasis. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Adjuvant aqueous ozone in the treatment of bisphosphonate induced necrosis of the jaws: report of two cases and long-term follow-up.

    PubMed

    Brozoski, M A; Lemos, C A; Da Graça Naclério-Homem, M; Deboni, M C Z

    2014-01-01

    Bisphosphonate induced necrosis of the jaws (BONJ) does not have a unique protocol of treatment and many therapeutic approaches have been arising in oral medicine with debatable results. A male and a female attended the University Oral Surgery Clinic presenting oral bone lesions induced by intravenous and oral bisphosphonates respectively as complications of dental extraction. Treatment included daily mouthwashes and weekly intra oral irrigations with 4 mg/L of aqueous-ozone, antibiotic therapy and sequential superficial debridment for sequestrectomies. Long-standing follow-ups showed complete mucosa covering of exposed bone area and resolution of purulent secretion. Antibacterial and antifungal properties of aqueous ozone may have played important roles in the treatment. The outcome measured intra oral examination and panoramic radiographs of the affected bone. The application of aqueous ozone daily mouthwashes and weekly professional irrigation were safe; free from adverse effects, easily of handling and worked as an important adjuvant therapeutic strategy for the treatment of BONJ.

  4. Effect of ethanolic extract of Premna corymbosa (Burm. f.) Rottl. & Willd. leaves in complete Freund's adjuvant-induced arthritis in Wistar albino rats.

    PubMed

    Karthikeyan, M; Deepa, K

    2010-01-01

    Premna corymbosa (Burm.f.) Rottl. & Willd. (Verbenaceae) is a small tree used in traditional medicine for rheumatic disorders and it is the one of the ingredient in many ayurvedic preparations available in the market for inflammatory disorder uses. The aim of this work was to evaluate the acute toxicity and anti-arthritic activity of P. corymbosa ethanolic extract (PCEE) in experimental animals. In the acute toxicity study, a single dose of PCEE, 2000 mg kg(-1) body weight p.o., was administered. The animals observed for 48 h showed no clinical signs, no mortality, and the extract was found to be safe. To evaluate the anti-arthritic activity of PCEE in Complete Freund's Adjuvant (CFA)-induced arthritis in rats were conducted. The results indicated that the long-term treatment significantly (p < .01) suppressed the development of chronic arthritis induced by CFA. This study established the anti-arthritic activity of P. corymbosa leaves.

  5. Targeted agents for adjuvant therapy of colon cancer.

    PubMed

    de Gramont, Aimery; Tournigand, Christophe; André, Thierry; Larsen, Annette K; Louvet, Christophe

    2006-12-01

    Adjuvant therapy for colorectal cancer consists primarily of combinations of 5-fluorouracil/leucovorin (5-FU/LV) (with infusional or bolus 5-FU) with oxaliplatin or oral capecitabine. The angiogenesis inhibitor bevacizumab and the epidermal growth factor receptor inhibitor cetuximab have shown activity when combined with 5-FU/LV-based regimens as first-line treatment of advanced disease and are currently being evaluated as part of adjuvant therapy in colon cancer. Bevacizumab is being evaluated in combination with FOLFOX4 (5-FU/LV/oxaliplatin), FOLFOX6, or XELOX (capecitabine/oxaliplatin) in the National Surgical Adjuvant Breast and Bowel Project C08 trial, the AVANT (AVastin adjuvANT) trial, and the Intergroup Rectal Adjuvant trial. Cetuximab is being evaluated in combination with FOLFOX4 and FOLFOX6 in the North Central Cancer Treatment Group (NCCTG) N0147 trial and the Pan European Trials in Adjuvant Colon Cancer (PETTAC) 8 trial.

  6. Fenofibrate vs pioglitazone: Comparative study of the anti-arthritic potencies of PPAR-alpha and PPAR-gamma agonists in rat adjuvant-induced arthritis.

    PubMed

    Koufany, Meriem; Jouzeau, Jean-Yves; Moulin, David

    2014-01-01

    Rheumatoid arthritis is characterized by synovial hyperplasia, inflammatory infiltration, cartilage destruction and juxta-articular as well as generalized bone demineralization. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily which behave as ligand-activated transcription factors in response to endogenous fatty acids and eicosanoids or isotype selective synthetic compounds as fibrates and thiazolidinediones. Beyond their key role in lipid metabolism, increased evidence has shown a role of the three isotypes in inflammatory modulation. We and others demonstrated previously that PPAR-gamma agonists reduced the severity of experimental polyarthritis and the overall inflammatory-induced bone loss. To compare the anti-arthritic potencies of a PPAR-alpha agonist (fenofibrate, a lipid lowering drug) and a PPAR-gamma agonist (pioglitazone, formerly used as an antidiabetic drug) in rat adjuvant-induced arthritis. Male Lewis rats were sensitized by an intra-dermal injection of 1 mg complete Freund's adjuvant at the basis of the tail and were treated orally for 21 days with fenofibrate 100 mg/kg/day (FENO) or pioglitazone 30 mg/kg/day (PIO), or with vehicle only. Arthritis severity was evaluated by clinical observations (oedema, clinical score, body weight). Global and femoral bone mineral density (BMD), femoral bone mineral content (BMC) were measured by dual-energy X-ray absorptiometry (DEXA) before sensitization and at day 20. Synovial mRNA levels of IL-1beta and IL-6 were determined by real-time RT-PCR. Administration of fenofibrate (100mg/kg/d) and pioglitazone (30 mg/kg/d) significantly reduced hindpaw oedema and arthritis score. Treatment with fenofibrate exerted a better effect on clinical scoring. DEXA analysis revealed that pioglitazone and fenofibrate treatment to a greater extent, reduced inflammatory-bone loss and increased BMD versus vehicle-treated rats. Finally, we demonstrated that both agonists

  7. Liposomal adjuvants for human vaccines.

    PubMed

    Alving, Carl R; Beck, Zoltan; Matyas, Gary R; Rao, Mangala

    2016-06-01

    Liposomes are well-known as drug carriers, and are now critical components of two of six types of adjuvants present in licensed vaccines. The liposomal vaccine adjuvant field has long been dynamic and innovative, and research in this area is further examined as new commercial products appear in parallel with new vaccines. In an arena where successful products exist the potential for new types of vaccines with liposomal adjuvants, and alternative liposomal adjuvants that could emerge for new types of vaccines, are discussed. Major areas include: virosomes, constructed from phospholipids and proteins from influenza virus particles; liposomes containing natural and synthetic neutral or anionic phospholipids, cholesterol, natural or synthetic monophosphoryl lipid A, and QS21 saponin; non-phospholipid cationic liposomes; and combinations and mixtures of liposomes and immunostimulating ingredients as adjuvants for experimental vaccines. Liposomes containing monophosphoryl lipid A and QS21 have considerable momentum that will result soon in emergence of prophylactic vaccines to malaria and shingles, and possible novel cancer vaccines. The licensed virosome vaccines to influenza and hepatitis A will be replaced with virosome vaccines to other infectious diseases. Alternative liposomal formulations are likely to emerge for difficult diseases such as tuberculosis or HIV-1 infection.

  8. The protective effects of curculigoside A on adjuvant-induced arthritis by inhibiting NF-кB/NLRP3 activation in rats.

    PubMed

    Ding, Huimin; Gao, Gongming; Zhang, Li; Shen, Guowei; Sun, Wenjian; Gu, Zhangping; Fan, Weimin

    2016-01-01

    The purpose of this study was to investigate the protective effects of curculigoside A (CA) on adjuvant arthritis (AA) rats and explore its possible mechanisms. AA was induced by intradermal injection of Freund's complete adjuvant (FCA). Male SD rats were treated with CA(10 and 20mg/kg) from days 18 to 24 after immunization. The levels of interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) in serum were determined by ELISA. Moreover, the levels of super oxide dismutase (SOD) and malondialdehyde (MDA) were determined using commercial kits. In particular, NLRP3 inflammasome and NF-кB pathway were detected by Western blot. As expected, CA at 10 and 20mg/kg significantly relieved the hind paw swelling and arthritis index, reduced the levels of IL-6 IL-1β, PGE2, TNF-α, MDA and increased SOD activity in serum. In addition, CA effectively down-regulated the expression of NF-кB/NLRP3 pathway. These findings showed that CA exerted beneficial effects on rheumatoid arthritis in rats.

  9. CD40-activated B cells express full lymph node homing triad and induce T-cell chemotaxis: potential as cellular adjuvants.

    PubMed

    von Bergwelt-Baildon, Michael; Shimabukuro-Vornhagen, Alexander; Popov, Alexey; Klein-Gonzalez, Nela; Fiore, Francesca; Debey, Svenja; Draube, Andreas; Maecker, Britta; Menezes, Isaura; Nadler, Lee M; Schultze, Joachim L

    2006-04-01

    CD40-activated B cells (CD40-B cells) have previously been introduced as an alternative source of antigen-presenting cells for immunotherapy. CD40-B cells can prime naive and expand memory T cells, and they can be generated in large numbers from very small amounts of peripheral blood derived from healthy individuals or cancer patients alike. Administration of CD40-B cells as a cellular adjuvant would require these cells to migrate toward secondary lymphoid organs and attract T cells in situ, processes guided by specific chemokines and chemokine receptors. Here, we demonstrate that primary, human CD40-B cells express a pattern of adhesion molecules and chemokine receptors necessary for homing to secondary lymphoid organs and have the capacity to migrate to cognate ligands. Furthermore, we show that CD40-B cells express important T-cell attractants and induce strong T-cell chemotaxis. These findings further support the use of CD40-B cells as cellular adjuvant for cancer immunotherapy.

  10. Adjuvant effect of Cliptox on the protective immune response induced by an inactivated vaccine against foot and mouth disease virus in mice.

    PubMed

    Batista, A; Quattrocchi, V; Olivera, V; Langellotti, C; Pappalardo, J S; Di Giacomo, S; Mongini, C; Portuondo, D; Zamorano, P

    2010-08-31

    Foot and Mouth Disease (FMD) is an acute disease caused by Foot and Mouth Disease Virus (FMDV) which causes important economy losses, this is why it is necessary to obtain a vaccine that stimulates a rapid and long-lasting protective immune response. Cliptox is a mineral microparticle that in earlier studies has shown adjuvant activity against different antigens. In this study we have examined the effects of Cliptox on the magnitude and type of immunity elicited in response to inactivated FMDV (iFMDV) vaccine. It was demonstrated that iFMDV-Cliptox stimulates a specific antibody response detected in mucosal and in sera. The different isotype profiles elicited by inoculation with this vaccine indicate a Th1/Th2 response. Also, an increase in dendritic cells and macrophages in the spleen in comparison with the iFMDV vaccine iFMDV-Cliptox was detected. The Cliptox-iFMDV formulation was non toxic by using egg embryos and yielded increased protection against challenge with FMDV in the murine model. Our results show that the incorporation of Cliptox into FMDVi vaccine induces an increase of the specific protective immune response in mice and clearly indicate that Cliptox TM exert an (important) up-regulation on DC and MPhi. Additionally, Cliptox TM adjuvant can be used in vaccines for induction of mucosal immune response.

  11. Different HIV pox viral vector-based vaccines and adjuvants can induce unique antigen presenting cells that modulate CD8 T cell avidity.

    PubMed

    Trivedi, Shubhanshi; Jackson, Ronald J; Ranasinghe, Charani

    2014-11-01

    The lung-derived dendritic cell (LDC) recruitment following intranasal (i.n.) vaccination of different poxviral vector-based vaccines/adjuvants were evaluated to decipher how these factors influenced CD8(+) T cell avidity. Compared to the standard i.n. recombinant fowlpox virus (FPV)-HIV vaccination, the FPV-HIV IL-13Rα2 or IL-4Rα antagonist adjuvanted vaccines that induced higher avidity CD8(+) T cells, also recruited significantly elevated MHCII(+) CD11c(+) CD11b(+) CD103(-) CD64(-) MAR-1(-) conventional DC (cDCs) to the lung mucosae (hierarchy: IL-4R antagonist>IL-13Rα2>unadjuvanted). In contrast, elevated CD11b(-) CD103(+) LDCs were detected in animals that received recombinant HIV vaccinia virus (rVV) or Modified Vaccinia Ankara virus (MVA) vector-based vaccines. Adoptive transfer studies indicated that CD11b(-) CD103(+) LDCs significantly dampened HIV-specific CD8(+) T cell avidity compared to CD11b(+) CD103(-) LDCs. Collectively; our observations revealed that rFPV vector prime and transient inhibition of IL-4/IL-13 at the vaccination site favoured the recruitment of unique LDCs, associated with the induction of high quality immunity.

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

    PubMed

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

    2013-05-07

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

  13. A murine model of experimental autoimmune lens-induced uveitis using Klebsiella O3 lipopolysaccharide as a potent immunological adjuvant.

    PubMed Central

    Yokochi, T.; Fujii, Y.; Nakashima, I.; Asai, J.; Kiuchi, M.; Kojima, K.; Kato, N.

    1993-01-01

    Experimental autoimmune uveitis and finally panophthalmitis could be produced in mice by repeated immunization of syngeneic eyeball extract mixed with Klebsiella O3 lipopolysaccharide (KO3 LPS) as a powerful immunological adjuvant. No ocular lesions were produced in mice given eyeball extract emulsified in complete Freund's adjuvant (CFA), KO3 LPS alone or eyeball extract alone. Histopathological changes in the ocular lesions at the early stage after the second or tertiary immunization were characterized by infiltration with inflammatory cells in the ciliary body and iris. The iridocyclitis was followed by extensive infiltration of polymorphonuclear leucocytes (PMN) into the cornea, lens and the surrounding tissues after repeated immunization. Finally, these areas were replaced by granulomatous tissues infiltrated with mononuclear cells. On the other hand, the structure of the retina and sclera was partially preserved. Those mice exhibited production of autoantibodies and development of the delayed-type hypersensitivity (DTH) to syngeneic eyeball extract. Moreover, ocular lesions could be produced in normal recipient mice by transfer of sensitized lymphocytes from hyperimmunized mice. Therefore, it was suggested that the ocular lesions produced by repeated immunization with the mixture of eyeball extract and KO3 LPS were due to the autoimmune mechanism. This might be useful to model immunological phenomena in the pathogenesis of human phacoantigenic uveitis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8292555

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

    PubMed

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

    2011-07-01

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

  15. Effects of Adjuvant-Induced Inflammation on Disposition of Diclofenac and Its Metabolites in Perfused Rat Liver.

    PubMed

    Uraki, Misato; Kawase, Atsushi; Sayama, Hiroyuki; Matsushima, Yuka; Iwaki, Masahiro

    2017-04-01

    The reactive metabolites of diclofenac (DF) such as 1-O-acyl glucuronide (DF-Glu) are hypothesized to result in idiosyncratic hepatotoxicity. However, it is unclear whether inflammation affects the hepatic disposition of DF and its metabolites. To clarify the alterations in the disposition of DF and its metabolites in inflammatory conditions, we performed in situ perfused rat liver experiments. Using adjuvant arthritis rats as a model of inflammation, the elimination of DF, 4'-hydroxydiclofenac, and DF-Glu from the perfusate was observed to be delayed in comparison with the control. Parameter sensitivity analysis for hepatic DF disposition revealed that the area under the plasma concentration-time curve (AUC) and the maximum concentration (Cmax) of DF-Glu in the liver markedly increased along with a decrease in intrinsic excretion clearance of DF-Glu (CLint,bile,Glu) and an increase in intrinsic glucuronidation clearance (CLint,Glu) of DF-Glu. It is possible that the elimination of DF-Glu from the perfusate in adjuvant arthritis rats was delayed via reduction of biliary excretion of DF-Glu. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  16. Chemotherapy, IL-12 gene therapy and combined adjuvant therapy of HPV 16-associated MHC class I-proficient and -deficient tumours.

    PubMed

    Indrová, Marie; Bieblová, Jana; Jandlová, Tána; Vonka, Vladimír; Pajtasz-Piasecka, Elzbieta; Reinis, Milan

    2006-01-01

    Moderately immunogenic HPV 16-associated murine tumour cell line mimicking human HPV 16-associated neoplasms TC-1 (MHC class I(+)) and its variants, TC-1/P3C10 and TC-1/A9, with a marked down-regulation of MHC I molecules, were used to examine the effect of local interleukin 12 (IL-12) gene therapy for the treatment of early tumour transplants and minimal residual tumour disease obtained after cytoreductive chemotherapy (CMRTD). Experiments were designed to examine whether down-regulation of MHC class I molecules plays a role during chemotherapy and gene therapy of early tumour transplants. It was found that peritumoral administration of IL-12-producing tumour cell vaccines (single dose, day 8 after tumour cell administration) inhibited the growth of both TC-1 (MHC class I positive) tumours and their MHC class I-deficient variants. To investigate the antitumour effects in a clinically relevant setting, IL-12 gene therapy was utilised for the treatment of minimal residual tumour disease after cytoreductive chemotherapy. Intra-peritoneal treatment of tumour-bearing mice with ifosfamide derivative, CBM-4A, produced a significant tumour-inhibitory effect. This treatment was followed by peritumoral s.c. administration of genetically modified TC-1 (MHC class I positive) or MK16/I/IIIABC (MHC class I negative) vaccines producing IL-12 (single dose, day 7 after chemotherapy) or with recombinant interleukin 12 (rIL-12) in two cycles of 5 daily doses (days 8-19) after chemotherapy. This combined therapy significantly inhibited the growth of TC-1 and TC-1/A9 (MHC class I-) tumours. When the combined therapy of TC-1 (MHC class I positive) tumours was followed by peritumoral administration of bone marrow dendritic cell (BMDC) vaccines, the IL-12-mediated inhibitory effect was significantly boosted. In the next set of experiments, the impacts of chemotherapy and IL-12 adjuvant therapy on MHC class I surface expression were assessed. Chemotherapy and gene therapy of tumours led

  17. The fluence effects of low-level laser therapy on inflammation, fibroblast-like synoviocytes, and synovial apoptosis in rats with adjuvant-induced arthritis.

    PubMed

    Hsieh, Yueh-Ling; Cheng, Yu-Jung; Huang, Fang-Chuen; Yang, Chen-Chia

    2014-12-01

    The aim of this study was to evaluate the effect of low-level laser therapy (LLLT) operating at low and high fluences on joint inflammation, fibroblast-like synoviocytes (FLS), and synovial apoptosis in rats with adjuvant-induced arthritis. Rheumatoid arthritis (RA) is characterized by pronounced inflammation and FLS proliferation within affected joints. Certain data indicate that LLLT is effective in patients with inflammation caused by RA; however, the fluence effects of LLLT on synovium are unclear. Monoarthritis was induced in adult male Sprague-Dawley rats (250-300 g) via intraarticular injection of complete Freund's adjuvant (CFA) into the tibiotarsal joint. Animals were irradiated 72 h after CFA administration with a 780 nm GaAlAs laser at 4.5 J/cm2 (30 mW, 30 sec/spot) and 72 J/cm2 (80 mW, 180 sec/spot) daily for 10 days. After LLLT, the animals were euthanized and their arthritic ankles were collected for histopathological analysis, immunoassays of tumor necrosis factor (TNF)-α, matrix metallopeptidase (MMP)3 and 5B5, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. LLLT at a fluence of 4.5 J/cm2 significantly reduced infiltration of inflammatory cells and expressions of TNF-α-, MMP3- and 5B5-like immunoreactivities, as well as resulting in more TUNEL-positive apoptotic cells in the synovium. No significant changes were observed in these biochemicals and inflammation in arthritic animals treated with 72 J/cm2. LLLT with low fluence is highly effective in reducing inflammation to sites of injury by decreasing the numbers of FLS, inflammatory cells, and mediators in the CFA-induced arthritic model. These data will be of value in designing clinical trials of LLLT for RA.

  18. No significant differences in the breadth of the foot-and-mouth disease serotype A vaccine induced antibody responses in cattle, using different adjuvants, mixed antigens and different routes of administration.

    PubMed

    Tekleghiorghis, Tesfaalem; Weerdmeester, Klaas; van Hemert-Kluitenberg, Froukje; Moormann, Rob J M; Dekker, Aldo

    2014-09-15

    Inactivated whole virus foot-and-mouth disease (FMD) vaccines are used worldwide for protection against FMD, but not all vaccines induce protection against all genetic variants of the same FMD virus serotype. The aim of this study is to investigate whether the "breadth" of the antibody response against different strains of the same FMD virus serotype in cattle could be improved by using a different adjuvant, a mix of antigens and/or different routes of administration. To this end, six groups of five cattle were vaccinated with different FMD virus serotype A strain vaccines formulated with Montanide ISA 206 VG adjuvant. Antibody responses for homologous and heterologous cross-reactivity against a panel of 10 different FMD virus serotype A strains were tested by a liquid-phase blocking ELISA. Results of cattle vaccinated with ISA 206 VG adjuvanted vaccine were compared with results obtained in a previous study using aluminium hydroxide-saponin adjuvant. No significant effect of adjuvant on the breadth of the antibody response was observed, neither for mixing of antigens nor for the route of administration (subcutaneous vs. intradermal). Comparison of antigen payload, however, increased both homologous and heterologous titres; a 10-fold higher antigen dose resulted in approximately four times higher titres against all tested strains. Our study shows that breadth of the antibody response depends mainly on the vaccine strain; we therefore propose that, for vaccine preparation, only FMD virus strains are selected that, among other important characteristics, will induce a wide antibody response to different field strains.

  19. [Adjuvant dermato-cosmetic acne therapy].

    PubMed

    Bayerl, Christiane; Degitz, Klaus; Meigel, Eva; Kerscher, Martina

    2010-03-01

    Adjuvant dermato-cosmetic therapy in acne is an essential part of the concept of treating acne after initiation and during maintenance therapy. Those are mechanical peeling, chemical peeling and its combination. It needs supervision by an experienced dermatologist.

  20. Chemotherapy-induced neutropenia during adjuvant treatment for cervical cancer patients: development and validation of a prediction model

    PubMed Central

    Huang, Kecheng; Luo, Aiyue; Li, Xiong; Li, Shuang; Wang, Shixuan

    2015-01-01

    An artificial neuron network (ANN) model combining both the genetic risk factors and clinical factorsmay be effective in prediction of chemotherapy-induced adverse events. Purpose: To identify genetic factors and clinical factors associated with bone marrow suppression in cervical cancer patient, and to build a model for chemotherapy-induced neutropenia prediction. Methods: We performed a genome wide association study on a cohort to identify genetic determinants. Samples were genotyped using the Axiom CHB 1.0. The primary analyses focused on the scan of 657178 single-nucleotide polymorphisms (SNPs). Artificial neural network were used to integrating clinical factors and genetic factors to predict the occurrence of neutropenia. Results: 32 variants associated with neutropenia in the patients after chemotherapy were found (P<1 × 10-4). During internal validation and external validation, artificial neural network performed well in predicting neutropenia with considerable accuracy, which is 88.9% and 81.7% respectively. ROC analysis had acceptable areas under the curve of 0.897 for the internal validation sample and 0.782 for the external validation sample. Conclusion: Neutropenia may be associated with both genetic factors and clinical factors. Our study found that the artificial neural networks model based on the multiple risk factors jointly, can effectively predict the occurring of neutropenia, which provides some guidance before the starting of chemotherapy. PMID:26379877

  1. Advax™, a polysaccharide adjuvant derived from delta inulin, provides improved influenza vaccine protection through broad-based enhancement of adaptive immune responses

    PubMed Central

    Honda-Okubo, Yoshikazu; Saade, Fadi; Petrovsky, Nikolai

    2012-01-01

    Advax™ adjuvant is derived from inulin, a natural plant-derived polysaccharide that when crystallized in the delta polymorphic form, becomes immunologically active. This study was performed to assess the ability of Advax™ adjuvant to enhance influenza vaccine immunogenicity and protection. Mice were immunized with influenza vaccine alone or combined with Advax™ adjuvant. Immuno-phenotyping of the anti-influenza response was performed including antibody isotypes, B-cell ELISPOT, CD4 and CD8 T-cell proliferation, influenza-stimulated cytokine secretion, DTH skin tests and challenge with live influenza virus. Advax™ adjuvant increased neutralizing antibody and memory B-cell responses to influenza. It similarly enhanced CD4 and CD8 T-cell proliferation and increased influenza-stimulated IL-2, IFN-γ, IL-5, IL-6, and GM-CSF responses. This translated into enhanced protection against mortality and morbidity in mice. Advax™ adjuvant provided significant antigen dose-sparing compared to influenza antigen alone. Protection could be transferred from mice that had received Advax™-adjuvanted vaccine to naïve mice by immune serum. Enhanced humoral and T-cell responses induced by Advax™-formulated vaccine were sustained 12 months post-immunization. Advax™ adjuvant had low reactogenicity and no adverse events were identified. This suggests Advax™ adjuvant could be a useful influenza vaccine adjuvant. PMID:22728225

  2. Cytokines: The Future of Intranasal Vaccine Adjuvants

    PubMed Central

    Thompson, Afton L.; Staats, Herman F.

    2011-01-01

    Due to its potential as an effective, needle-free route of immunization for use with subunit vaccines, nasal immunization continues to be evaluated as a route of immunization in both research and clinical studies. However, as with other vaccination routes, subunit vaccines often require the addition of adjuvants to induce potent immune responses. Unfortunately, many commonly used experimental vaccine adjuvants, such as cholera toxin and E. coli heat-labile toxin, are too toxic for use in humans. Because new adjuvants are needed, cytokines have been evaluated for their ability to provide effective adjuvant activity when delivered by the nasal route in both animal models and in limited human studies. It is the purpose of this paper to discuss the potential of cytokines as nasal vaccine adjuvants. PMID:21826181

  3. Changes in immunological parameters after combination adjuvant therapy with intravenous DTIC, ACNU, and VCR, and local injection of IFN-beta (DAV + IFN-beta therapy) into malignant melanoma.

    PubMed

    Umeda, T; Aoki, K; Yokoyama, A; Ohara, H; Hayashi, O; Tanaka, K; Nishioka, K

    1998-09-01

    Combination adjuvant therapy with intravenous dimethyl triazeno imidazole carboxamide (DTIC), 1-[4-amino-2-methyl-5-pyrimidinyl]-methyl-3-[2-chloroethyl]-3-nitrosoure a hydrochloride (ACNU) and vincristine (VCR) and local injection of interferon-beta (IFN-beta) (DAV + IFN-beta therapy) has been widely applied to treat malignant melanoma, and its therapeutic effect is accepted in Japan. Natural killer (NK) activity, CD4+ and CD8+ T cell counts, CD4/CD8 ratio, and white blood cell counts were analyzed before and after DAV + IFN-beta therapy in order to validate its efficacy. After DAV + IFN-beta therapy, the CD4/CD8 ratio was elevated; however, numbers of both CD4+ and CD8+ T cells and NK activity were consecutively depressed. Peripheral lymphocytes were also decreased, possibly by myelosuppression due to the DAV therapy. The posttreatment suppression of NK activity appeared in spite of the administration of IFN-beta. It is suggested that a more effective adjuvant immunomodulator should be introduced to improve the therapeutic effect of the combination adjuvant chemotherapy in malignant melanoma.

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

    PubMed Central

    Zamani Gandomani, Mahdi; Forouzandeh Malati, Elaheh

    2014-01-01

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

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

    PubMed

    Zamani Gandomani, Mahdi; Forouzandeh Malati, Elaheh

    2014-01-01

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

  6. Postural Orthostatic Tachycardia With Chronic Fatigue After HPV Vaccination as Part of the "Autoimmune/Auto-inflammatory Syndrome Induced by Adjuvants": Case Report and Literature Review.

    PubMed

    Tomljenovic, Lucija; Colafrancesco, Serena; Perricone, Carlo; Shoenfeld, Yehuda

    2014-01-01

    We report the case of a 14-year-old girl who developed postural orthostatic tachycardia syndrome (POTS) with chronic fatigue 2 months following Gardasil vaccination. The patient suffered from persistent headaches, dizziness, recurrent syncope, poor motor coordination, weakness, fatigue, myalgias, numbness, tachycardia, dyspnea, visual disturbances, phonophobia, cognitive impairment, insomnia, gastrointestinal disturbances, and a weight loss of 20 pounds. The psychiatric evaluation ruled out the possibility that her symptoms were psychogenic or related to anxiety disorders. Furthermore, the patient tested positive for ANA (1:1280), lupus anticoagulant, and antiphospholipid. On clinical examination she presented livedo reticularis and was diagnosed with Raynaud's syndrome. This case fulfills the criteria for the autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA). Because human papillomavirus vaccination is universally recommended to teenagers and because POTS frequently results in long-term disabilities (as was the case in our patient), a thorough follow-up of patients who present with relevant complaints after vaccination is strongly recommended.

  7. Recombinant HPV16 E7 assembled into particles induces an immune response and specific tumour protection administered without adjuvant in an animal model

    PubMed Central

    2011-01-01

    Background The HPV16 E7 protein is both a tumour-specific and a tumour-rejection antigen, the ideal target for developing therapeutic vaccines for the treatment of HPV16-associated cancer and its precursor lesions. E7, which plays a key role in virus-associated carcinogenesis, contains 98 amino acids and has two finger-type structures which bind a Zn++ ion. The ability of an Escherichia coli-produced E7-preparation, assembled into particles, to induce protective immunity against a HPV16-related tumour in the TC-1-C57BL/6 mouse tumour model, was evaluated. Methods E7 was expressed in E. coli, purified via a one-step denaturing protocol and prepared as a soluble suspension state after dialysis in native buffer. The presence in the E7 preparation of particulate forms was analysed by non-reducing SDS-PAGE and negative staining electron microscopy (EM). The Zn++ ion content was analysed by mass-spectrometry. Ten μg of protein per mouse was administered to groups of animals, once, twice or three times without adjuvant. The E7-specific humoral response was monitored in mice sera using an E7-based ELISA while the cell-mediated immune response was analysed in mice splenocytes with lymphoproliferation and IFN-γ ELISPOT assays. The E7 immunized mice were challenged with TC-1 tumour cells and the tumour growth monitored for two months. Results In western blot analysis E7 appears in multimers and high molecular mass oligomers. The EM micrographs show the protein dispersed as aggregates of different shape and size. The protein appears clustered in micro-, nano-aggregates, and structured particles. Mice immunised with this protein preparation show a significant E7-specific humoral and cell-mediated immune response of mixed Th1/Th2 type. The mice are fully protected from the tumour growth after vaccination with three E7-doses of 10 μg without any added adjuvant. Conclusions This report shows that a particulate form of HPV16 E7 is able to induce, without adjuvant, an E7-specific

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

    PubMed

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

    2015-01-01

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

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

    SciTech Connect

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

    2013-04-15

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

    Yu, Ruili; Yang, Bo; Chi, Xiaohua; Cai, Lili; Liu, Cui; Yang, Lei; Wang, Xueyan; He, Peifeng; Lu, Xuechun

    2017-01-01

    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 results were found when non-RCT and RCTs were pooled (pooled HR =0.623, 95% CI =0.516–0.752, P<0.001). Adjuvant CIK cell-based immunotherapy is a promising therapeutic approach that can improve overall survival and reduce recurrence in patients with HCC. PMID:28360510

  12. Vaccination with Clostridium perfringens recombinant proteins in combination with Montanide™ ISA 71 VG adjuvant increases protection against experimental necrotic enteritis in commercial broiler chickens

    USDA-ARS?s Scientific Manuscript database

    This study was performed to compare four Clostridium perfringens recombinant proteins as vaccine candidates using the Montanide™ ISA 71 VG adjuvant in an experimental model of necrotic enteritis. Broiler chickens were immunized with clostridial recombinant proteins with ISA 71 VG, and intestinal le...

  13. Evaluation of Three Experimental Bovine Viral Diarrhea Virus Killed Vaccines Adjuvanted with Combinations of QuilA Cholesterol and Dimethyldioctadecylammonium (DDA) Bromide

    USDA-ARS?s Scientific Manuscript database

    Bovine viral diarrhea virus (BVDV) infections cause respiratory, reproductive, and enteric disease in cattle. Vaccination raises herd resistance and then limits the spread of bovine viral diarrhea viruses (BVDV) among cattle. The goal of this research was to evaluate new adjuvants, consisting of c...

  14. An innovative approach to induce cross-protective immunity against porcine reproductive and respiratory syndrome virus in the lungs of pigs through adjuvanted nanotechnology-based vaccination.

    PubMed

    Binjawadagi, Basavaraj; Dwivedi, Varun; Manickam, Cordelia; Ouyang, Kang; Torrelles, Jordi B; Renukaradhya, Gourapura J

    2014-01-01

    Porcine reproductive and respiratory syndrome (PRRS) is an economically devastating respiratory disease of pigs. The disease is caused by the PRRS virus (PRRSV), an Arterivirus which is a highly mutating RNA virus. Widely used modified live PRRSV vaccines have failed to prevent PRRS outbreaks and reinfections; moreover, safety of the live virus vaccines is questionable. Though poorly immunogenic, inactivated PRRSV vaccine is safe. The PRRSV infects primarily the lung macrophages. Therefore, we attempted to strengthen the immunogenicity of inactivated/killed PRRSV vaccine antigens (KAg), especially in the pig respiratory system, through: 1) entrapping the KAg in biodegradable poly(lactic-co-glycolic acid) nanoparticles (NP-KAg); 2) coupling the NP-KAg with a potent mucosal adjuvant, whole cell lysate of Mycobacterium tuberculosis (M. tb WCL); and 3) delivering the vaccine formulation twice intranasally to growing pigs. We have previously shown that a single dose of NP-KAg partially cleared the challenged heterologous PRRSV. Recently, we reported that NP-KAg coupled with unentrapped M. tb WCL significantly cleared the viremia of challenged heterologous PRRSV. Since PRRSV is primarily a lung disease, our goal in this study was to investigate lung viral load and various immune correlates of protection at the lung mucosal surfaces and its parenchyma in vaccinated heterologous PRRSV-challenged pigs. Our results indicated that out of five different vaccine-adjuvant formulations, the combination of NP-KAg and unentrapped M. tb WCL significantly cleared detectable replicating infective PRRSV with a tenfold reduction in viral RNA load in the lungs, associated with substantially reduced gross and microscopic lung pathology. Immunologically, strong humoral (enhanced virus neutralization titers by high avidity antibodies) and cell-mediated immune responses (augmented population of interferon-γ secreting CD4(+) and CD8(+) lymphocytes and reduced secretion of immunosuppressive

  15. Sequential adjuvant chemoradiotherapy-induced diffuse alveolar haemorrhage in a patient with breast cancer successfully treated with corticosteroid plus recombinant human soluble thrombomodulin.

    PubMed

    Kitajima, Takamasa; Marumo, Satoshi; Maeshima, Yurina; Fukui, Motonari

    2016-10-28

    The effective treatment for corticosteroid (CS)-refractory sequential chemoradiotherapy (CRT)-induced lung injury has not been established. We report a case of sequential CRT-induced diffuse alveolar haemorrhage (DAH) successfully treated with CS therapy plus recombinant human soluble thrombomodulin (rhTM). A 69-year-old woman was treated with sequential adjuvant CRT for early-stage breast cancer. After sequential CRT, she suffered from progressive dyspnoea. Chest CT scan showed consolidations in the irradiation field and diffuse ground-glass attenuations in the non-irradiation regions. We suspected sequential CRT-induced DAH because of increased haemosiderin-laden macrophages in bronchoalveolar lavage fluid. Her clinical conditions did not improve with high-dose CS therapy. Therefore, rhTM was added, and her disease and serum high-mobility group box-1 levels improved rapidly. Therefore, rhTM plus CS might be a safe and effective treatment for sequential CRT-induced lung injury, although further study is necessary to validate these findings. 2016 BMJ Publishing Group Ltd.

  16. A comparative study on the efficacy of rofecoxib in monoarticular arthritis induced by latex of Calotropis procera and Freund's complete adjuvant.

    PubMed

    Kumar, V L; Roy, S; Sehgal, R; Padhy, B M

    2006-03-01

    The role of prostaglandins in Calotropis procera latex induced inflammation and hyperalgesia has been well established. The acute inflammation induced by the dried latex (DL) of this plant could be effectively ameliorated by standard anti-inflammatory drugs. In present study we have evaluated the efficacy of rofecoxib, a COX-2 inhibitor in monoarthritis induced by intra-articular injection of DL and compared it with that against Freund's Complete Adjuvant (FCA). DL and FCA were injected into the right ankle joint of the rat and the joint diameter was measured by a micrometer screw gauge on day 0, 4, 8, 12, 20 and 28. Concomitantly the hyperalgesic response was also evaluated by motility test, stair climbing ability test, dorsal flexion pain test and compression test. The effect of rofecoxib was evaluated on these parameters in both the models. Both DL and FCA produced peak inflammation on day 4 that was associated with decreased pain threshold and functional impairment. Although rofecoxib was more effective in improving motility in the DL model, its effect on joint inflammation, hyperalgesia and stair climbing ability was comparable in both the models. Thus, our study indicates that DL induced monoarthritis could be used as a model for the screening and evaluation of anti-inflammatory and anti-arthritic drugs.

  17. Pulsed radiofrequency reduced complete Freund's adjuvant-induced mechanical hyperalgesia via the spinal c-Jun N-terminal kinase pathway.

    PubMed

    Chen, Kuan-Hung; Yang, Chien-Hui; Juang, Sin-Ei; Huang, Hui-Wen; Cheng, Jen-Kun; Sheen-Chen, Shyr-Ming; Cheng, Jiin-Tsuey; Lin, Chung-Ren

    2014-03-01

    Pulsed radiofrequency (PRF) treatment involves the pulsed application of a radiofrequency electric field to a nerve. The technology offers pain relief for patients suffering from chronic pain who do not respond well to conventional treatments. We tested whether PRF treatment attenuated complete Freund's adjuvant (CFA) induced inflammatory pain. The profile of spinal c-Jun N-terminal kinases (JNKs) phosphorylation was evaluated to elucidate the potential mechanism. Injection of CFA into the unilateral hind paw of rats induced mechanical hyperalgesia in both the ipsilateral and contralateral hind paws. We administered 500-kHz PRF treatment in 20-ms pulses, at a rate of 2 Hz (2 pulses per second) either to the sciatic nerve in the mid-thigh, or to the L4 anterior primary ramus just distal to the intervertebral foramen in both the CFA group and no-PRF group rats. Tissue samples were examined at 1, 3, 7, and 14 days following PRF treatments. Behavioral studies showed that PRF applied close to the dorsal root ganglion (DRG) significantly attenuated CFA-induced mechanical hyperalgesia compared to no-PRF group (P < .05). And western blotting revealed significant attenuation of the activation of JNK in the spinal dorsal horn compared to no-PRF group animals (P < .05). Application of PRF close to DRG provides an effective treatment for CFA-induced persistent mechanical hyperalgesia by attenuating JNK activation in the spinal dorsal horn.

  18. Protective effects of total flavonoids of Astragalus against adjuvant-induced arthritis in rats by regulating OPG/RANKL/NF-κB pathway.

    PubMed

    Liu, Xin-Yu; Xu, Lu; Wang, Ying; Li, Jin-Xia; Zhang, Yu; Zhang, Chong; Wang, Sha-Sha; Zhang, Xue-Mei

    2017-03-01

    Astragalus membranaceus Bunge is one of the oldest and most frequently used crude herbs in traditional Chinese medicine. The total flavonoids of Astragalus (TFA) are the main active components isolated from Astragalus membranaceus Bunge. Our recent study has shown its potential immunomodulatory and anti-inflammatory effects in vivo and in vitro. However, its anti-arthritic effects and mechanisms of action involved have not been elucidated. The aim of this study was to evaluate the protective effects and possible mechanisms of TFA on Freund's complete adjuvant (FCA)-induced arthritis in rats. Wistar rats were intradermally injected FCA into the right hind metatarsal footpads to establish adjuvant-arthritic model. The rats were intragastrically administered daily with TFA at 25, 50 and 100mg/kg for 28days after FCA induction. Body weight, primary paw swelling, arthritis index, thymus and spleen indices were measured. The levels of serum tumor necrosis factor (TNF)-α, interleukin (IL)-1β, prostaglandin (PG)E2, osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) were determined using ELISA. Histopathological changes and scores in joint tissues were examined using hematoxylin and eosin (H&E). The expression of nuclear factor (NF)-κB p65 in synovial tissues was assayed using immunohistochemical method. TFA significantly increased body weight, attenuated primary paw swelling and arthritis index, decreased thymus and spleen indices of rats induced by FCA. Furthermore, TFA significantly inhibited serum TNF-α, IL-1β, PGE2 and RANKL production, and promoted serum OPG production and OPG/RANKL ratio of rats induced by FCA. Histopathological examination indicated that TFA significantly attenuated inflammatory cell infiltration, synovial hyperplasia, pannus formation, and bone and cartilage damage. Immunohistochemical assay indicated that TFA inhibited NF-κB p65 expression in synovial tissues of rats induced by FCA. These results suggest that

  19. Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants

    PubMed Central

    Olafsdottir, Thorunn A.; Lindqvist, Madelene; Nookaew, Intawat; Andersen, Peter; Maertzdorf, Jeroen; Persson, Josefine; Christensen, Dennis; Zhang, Yuan; Anderson, Jenna; Khoomrung, Sakda; Sen, Partho; Agger, Else Marie; Coler, Rhea; Carter, Darrick; Meinke, Andreas; Rappuoli, Rino; Kaufmann, Stefan H. E.; Reed, Steven G.; Harandi, Ali M.

    2016-01-01

    A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants. PMID:27958370

  20. Flagellin a toll-like receptor 5 agonist as an adjuvant in chicken vaccines.

    PubMed

    Gupta, Shishir Kumar; Bajwa, Preety; Deb, Rajib; Chellappa, Madhan Mohan; Dey, Sohini

    2014-03-01

    Chicken raised under commercial conditions are vulnerable to environmental exposure to a number of pathogens. Therefore, regular vaccination of the flock is an absolute requirement to prevent the occurrence of infectious diseases. To combat infectious diseases, vaccines require inclusion of effective adjuvants that promote enhanced protection and do not cause any undesired adverse reaction when administered to birds along with the vaccine. With this perspective in mind, there is an increased need for effective better vaccine adjuvants. Efforts are being made to enhance vaccine efficacy by the use of suitable adjuvants, particularly Toll-like receptor (TLR)-based adjuvants. TLRs are among the types of pattern recognition receptors (PRRs) that recognize conserved pathogen molecules. A number of studies have documented the effectiveness of flagellin as an adjuvant as well as its ability to promote cytokine production by a range of innate immune cells. This minireview summarizes our current understanding of flagellin action, its role in inducing cytokine response in chicken cells, and the potential use of flagellin as well as its combination with other TLR ligands as an adjuvant in chicken vaccines.

  1. Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants

    NASA Astrophysics Data System (ADS)

    Olafsdottir, Thorunn A.; Lindqvist, Madelene; Nookaew, Intawat; Andersen, Peter; Maertzdorf, Jeroen; Persson, Josefine; Christensen, Dennis; Zhang, Yuan; Anderson, Jenna; Khoomrung, Sakda; Sen, Partho; Agger, Else Marie; Coler, Rhea; Carter, Darrick; Meinke, Andreas; Rappuoli, Rino; Kaufmann, Stefan H. E.; Reed, Steven G.; Harandi, Ali M.

    2016-12-01

    A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants.

  2. Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants.

    PubMed

    Olafsdottir, Thorunn A; Lindqvist, Madelene; Nookaew, Intawat; Andersen, Peter; Maertzdorf, Jeroen; Persson, Josefine; Christensen, Dennis; Zhang, Yuan; Anderson, Jenna; Khoomrung, Sakda; Sen, Partho; Agger, Else Marie; Coler, Rhea; Carter, Darrick; Meinke, Andreas; Rappuoli, Rino; Kaufmann, Stefan H E; Reed, Steven G; Harandi, Ali M

    2016-12-13

    A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants.

  3. A metoprolol-terbinafine combination induced bradycardia.

    PubMed

    Bebawi, Emmanuel; Jouni, Suhail S; Tessier, Andrée-Anne; Frenette, Anne Julie; Brindamour, Dave; Doré, Maxime

    2015-09-01

    To report a sinus bradycardia induced by metoprolol and terbinafine drug-drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient's sinus bradycardia and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to bisoprolol and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol's clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia.

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

    PubMed

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

    2015-06-01

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

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

    SciTech Connect

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

    1991-09-01

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

  6. Immunization with antigenic extracts of Leishmania associated with Montanide ISA 763 adjuvant induces partial protection in BALB/c mice against Leishmania (Leishmania) amazonensis infection.

    PubMed

    Cargnelutti, Diego Esteban; Salomón, María Cristina; Celedon, Verónica; García Bustos, María Fernanda; Morea, Gastón; Cuello-Carrión, Fernando Darío; Scodeller, Eduardo Alberto

    2016-02-01

    A proper adjuvant has a relevant role in vaccine formulations to generate an effective immune response. In this study, total Leishmania antigen (TLA) formulated with Montanide ISA 763 or R848 as adjuvants were evaluated as a first generation Leishmania vaccine in a murine model. Immunization protocols were tested in BALB/c mice with a subcutaneous prime/boost regimen with an interval of 3 weeks. Mice immunized with unadjuvanted TLA and phosphate-buffered saline (PBS) served as control groups. On Day 21 and Day 36 of the protocol, we evaluated the humoral immune response induced by each formulation. Fifteen days after the boost, the immunized mice were challenged with 1 × 10(5) promastigotes of Leishmania (Leishmania) amazonensis in the right footpad (RFP). The progress of the infection was followed for 10 weeks; at the end of this period, histopathological studies were performed in the RFP. Vaccines formulated with Montanide ISA 763 generated an increase in the production of immunoglobulin G (IgG; p < 0.05) compared with the control group. There were no statistically significant differences in IgG1 production between the study groups. However, immunization with TLA-Montanide ISA 763 resulted in an increase in IgG2a compared to the unadjuvanted control (p < 0.001). Also noteworthy was the fact that a significant reduction in swelling and histopathological damage of the RFP was recorded with the Montanide ISA 763 formulation. We conclude that the immunization of BALB/c mice with a vaccine formulated with TLA and Montanide ISA 763 generated a protective immune response against L. (L.) amazonensis, characterized by an intense production of IgG2a. Copyright © 2014. Published by Elsevier B.V.

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

    PubMed

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

    2016-01-27

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

  8. MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults.

    PubMed

    Banzhoff, Angelika; Gasparini, Roberto; Laghi-Pasini, Franco; Staniscia, Tommaso; Durando, Paolo; Montomoli, Emanuele; Capecchi, Pier Leopoldo; Capecchi, Pamela; di Giovanni, Pamela; Sticchi, Laura; Gentile, Chiara; Hilbert, Anke; Brauer, Volker; Tilman, Sandrine; Podda, Audino

    2009-01-01

    Pathogenic avian influenza virus (H5N1) has the potential to cause a major global pandemic in humans. Safe and effective vaccines that induce immunologic memory and broad heterotypic response are needed. Healthy adults aged 18-60 and > 60 years (n = 313 and n = 173, respectively) were randomized (1:1) to receive two primary and one booster injection of 7.5 microg or 15 microg doses of a subunit MF59-adjuvanted H5N1 (A/Vietnam/1194/2004) (clade 1) vaccine. Safety was monitored until 6 months after booster. Immunogenicity was assessed by hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization assays (MN). Mild injection-site pain was the most common adverse reaction. No serious adverse events relating to the vaccine were reported. The humoral immune responses to 7.5 microg and 15 microg doses were comparable. The rates for seroprotection (HI>40; SRH>25 mm(2); MN > or = 40) after the primary vaccination ranged 72-87%. Six months after primary vaccination with the 7.5 microg dose, 18% and 21% of non-elderly and elderly adults were seroprotected; rates increased to 90% and 84%, respectively, after the booster vaccination. In the 15 microg group, seroprotection rates among non-elderly and elderly adults increased from 25% and 62% after primary vaccination to 92% and 88% after booster vaccination, respectively. A heterologous immune response to the H5N1/turkey/Turkey/05 strain was elicited after second and booster vaccinations. Both formulations of MF59-adjuvanted influenza H5N1 vaccine were well tolerated. The European Union requirement for licensure for pre-pandemic vaccines was met by the lower dose tested. The presence of cross-reactive antibodies to a clade 2 heterologous strain demonstrates that this vaccine may be appropriate for pre-pandemic programs. (ClinicalTrials.gov) NCT00311480.

  9. Role of Tachykinin 1 and 4 Gene-Derived Neuropeptides and the Neurokinin 1 Receptor in Adjuvant-Induced Chronic Arthritis of the Mouse

    PubMed Central

    Borbély, Éva; Hajna, Zsófia; Sándor, Katalin; Kereskai, László; Tóth, István; Pintér, Erika; Nagy, Péter; Szolcsányi, János; Quinn, John; Zimmer, Andreas; Stewart, James; Paige, Christopher; Berger, Alexandra; Helyes, Zsuzsanna

    2013-01-01

    Objective Substance P, encoded by the Tac1 gene, is involved in neurogenic inflammation and hyperalgesia via neurokinin 1 (NK1) receptor activation. Its non-neuronal counterpart, hemokinin-1, which is derived from the Tac4 gene, is also a potent NK1 agonist. Although hemokinin-1 has been described as a tachykinin of distinct origin and function compared to SP, its role in inflammatory and pain processes has not yet been elucidated in such detail. In this study, we analysed the involvement of tachykinins derived from the Tac1 and Tac4 genes, as well as the NK1 receptor in chronic arthritis of the mouse. Methods Complete Freund’s Adjuvant was injected intraplantarly and into the tail of Tac1−/−, Tac4−/−, Tacr1−/− (NK1 receptor deficient) and Tac1−/−/Tac4−/− mice. Paw volume was measured by plethysmometry and mechanosensitivity using dynamic plantar aesthesiometry over a time period of 21 days. Semiquantitative histopathological scoring and ELISA measurement of IL-1β concentrations of the tibiotarsal joints were performed. Results Mechanical hyperalgesia was significantly reduced from day 11 in Tac4−/− and Tacr1−/− animals, while paw swelling was not altered in any strain. Inflammatory histopathological alterations (synovial swelling, leukocyte infiltration, cartilage destruction, bone damage) and IL-1β concentration in the joint homogenates were significantly smaller in Tac4−/− and Tac1−/−/Tac4−/− mice. Conclusions Hemokinin-1, but not substance P increases inflammation and hyperalgesia in the late phase of adjuvant-induced arthritis. While NK1 receptors mediate its antihyperalgesic actions, the involvement of another receptor in histopathological changes and IL-1β production is suggested. PMID:23626716

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

    PubMed

    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

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

    PubMed Central

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

    2016-01-01

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

  12. Scopoletin suppresses IL-6 production from fibroblast-like synoviocytes of adjuvant arthritis rats induced by IL-1β stimulation.

    PubMed

    Dou, Yannong; Tong, Bei; Wei, Zhifeng; Li, Ying; Xia, Yufeng; Dai, Yue

    2013-12-01

    Scopoletin, a coumarin compound naturally occurring in many medicinal plants, has previously been demonstrated to ameliorate synovial inflammation and destruction of cartilage and bone in adjuvant arthritis (AA) rats. As interleukin (IL)-6 is critically involved in the initiation and development of rheumatoid arthritis (RA), the present study was performed to investigate the effect of scopoletin on IL-6 production from fibroblast-like synoviocytes (FLS) to get insight into its anti-RA mechanisms. FLS were isolated from synovial membrane tissues of AA rats, and stimulated with IL-1β (10 ng/mL). Scopoletin, at concentrations of 15, 30, and 60 μM, was shown to only moderately inhibit FLS proliferation, but dramatically reduce IL-6 production at both mRNA and protein levels. It also inhibited the phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), protein kinase C (PKC) and cAMP response element binding protein (CREB). These findings suggest that scopoletin exerts anti-RA action probably through suppressing IL-6 production from FLS via MAPK/PKC/CREB pathways.

  13. POLY IC IS THE MOST EFFECTIVE TOLL-LIKE RECEPTOR ADJUVANT FOR SIV GAG PROTEIN INDUCED T CELL RESPONSES IN NON-HUMAN PRIMATES

    PubMed Central

    Park, Haesun; Adamson, Lauren; Ha, Tae; Mullen, Karl; Hagen, Shoko I; Nogueron, Arys; Sylwester, Andrew W.; Axthelm, Michael K.; Legasse, Al; Piatak, Michael; Lifson, Jeffrey D.; McElrath, Juliana M.; Picker, Louis J.; Seder, Robert A.

    2013-01-01

    Prime-boost immunization with heterologous vaccines elicits potent cellular immunity. Here, we assessed the influence of various TLR ligands on SIV Gag-specific T cell immunity and protection following prime-boost immunization. Rhesus macaques (RM) were primed with SIV Gag protein emulsified in montanide ISA51 with or without TLR3 (polyinosinic-polycytidylic acid (Poly IC)), TLR4 (monophosphoryl lipid A (MPL)), TLR7/8, TLR9 (CpG) or TLR3 (Poly IC) combined with TLR7/8 ligands, then boosted with replication defective adenovirus 5 expressing SIV Gag (rAd5-Gag). After priming, RM that received SIV Gag protein plus Poly IC developed significantly higher frequencies of SIV Gag-specific CD4+ Th1 responses in blood and bronchoalveolar lavage fluid lymphocytes (BAL) compared to all other adjuvants, and low-level SIV Gag-specific CD8+ T cell responses. After the rAd5-Gag boost, the magnitude and breadth of SIV Gag-specific CD8+ T cell responses were significantly increased in RM primed with SIV Gag protein plus Poly IC, with or without the TLR7/8 ligand, or CpG. However, the anamnestic, SIV Gag-specific CD8+ T cell response to SIVmac251 challenge was not significantly enhanced by SIV Gag protein priming with any of the adjuvants. In contrast, the anamnestic SIV Gag-specific CD4+ T cell response in BAL was enhanced by SIV Gag protein priming with Poly IC or CpG, which correlated with partial control of early viral replication after SIVmac251 challenge. These results demonstrate that prime-boost vaccination with SIV Gag protein/Poly IC improves magnitude, breadth, and durability of CD4+ T cell immune responses, which may have a role in control of SIV viral replication. PMID:23509365

  14. A short hairpin RNA-based adjuvant targeting NF-κB repressor IκBα promotes migration of dermal dendritic cells to draining lymph nodes and antitumor CTL responses induced by DNA vaccination.

    PubMed

    Gálvez-Cancino, Felipe; Roco, Jonathan; Rojas-Colonelli, Nicole; Flores, Camila; Murgas, Paola; Cruz-Gómez, Sebastián; Oyarce, César; Varas-Godoy, Manuel; Sauma, Daniela; Lladser, Alvaro

    2017-07-24

    DNA vaccination is an attractive approach to elicit tumor-specific cytotoxic CD8(+) T lymphocytes (CTL), which can mediate protective immunity against tumors. To initiate CTL responses, antigen-encoding plasmids employed for DNA vaccination need to activate dendritic cells (DC) through the stimulation of DNA-sensing innate immune receptors that converge in the activation of the master transcription factor NF-κB. To this end, NF-κB repressor IκBα needs to be degraded, allowing NF-κB to translocate to the nucleus and transcribe proinflammatory target genes, as well as its repressor IκBα. Therefore, NF-κB activation is self-limited by de novo synthesis of IκBa, which sequesters NF-κB in the cytosol. Hence, we tested whether co-delivering a shRNA-based adjuvant able to silence IκBα expression would further promote DNA-induced NFκB activation, DC activation and tumor-protective CTL responses induced by DNA vaccination in a preclinical model. First, an IκBα-targeting shRNA plasmid (shIκBα) was shown to reduce IκBα expression and promote NFκB-driven transcription in vitro, as well as up-regulate inflammatory target genes in vivo. Then, we showed that intradermal DNA electroporation induced the migration of skin migratory dendritic cells to draining lymph nodes and maturation of dermal dendritic cells (dDC). Interestingly, shIκBα further promoted the migration of mature skin migratory dendritic cells, in particular dDC, which are specialized in antigen cross-presentation and activation of CD8(+) T cells. Consistently, mice vaccinated with a plasmid encoding the melanoma-associated antigen tyrosinase-related protein 2 (TRP2) in combination with shIκBα enhanced TRP2-specific CTL responses and reduced the number of lung melanoma foci in mice challenged with intravenous injection of B16F10 cells. Moreover, therapeutic vaccination with pTRP2 and shIκBα delayed the growth of B16F10 melanoma subcutaneous tumors. Our data suggest that adjuvants promoting

  15. Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox IV.

    PubMed

    Vincenzi, Bruno; Frezza, Anna Maria; Schiavon, Gaia; Spoto, Chiara; Silvestris, Nicola; Addeo, Raffaele; Catalano, Vincenzo; Graziano, Francesco; Santini, Daniele; Tonini, Giuseppe

    2013-05-01

    Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40 % of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration. One hundred sixty-nine completely resected colorectal cancer patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcaemia, hypomagnesaemia, hypoalbuminaemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, vitamin B(12) deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded. Incidence of neuropathy was found to be higher in patients with pre-treatment anaemia (p = 0.001), hypoalbuminaemia (p = 0.01) and hypomagnesaemia (p = 0.001) as well in those with habit to alcohol consumption (p = 0.003). Neuropathy durations were conversely associated with age, being longer in younger patients (p = 0.03), and again with hypoalbuminaemia (p = 0.04) and hypomagnesaemia (p = 0.002). No correlation was found with gender, hypocalcaemia, diabetes and CRF. The correlation between vitamin B(12) and folate levels and the development of neurotoxicity were not analysed because of the high number of missing data in the population. Age, anaemia, hypoalbuminaemia, hypomagnesaemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin-induced neuropathy.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-12-01

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

  18. Recombinant cholera toxin B subunit (rCTB) as a mucosal adjuvant enhances induction of diphtheria and tetanus antitoxin antibodies in mice by intranasal administration with diphtheria-pertussis-tetanus (DPT) combination vaccine.

    PubMed

    Isaka, Masanori; Komiya, Takako; Takahashi, Motohide; Yasuda, Yoko; Taniguchi, Tooru; Zhao, Yanqiu; Matano, Keiko; Matsui, Hideyuki; Maeyama, Jun-Ichi; Morokuma, Kazunori; Ohkuma, Kunio; Goto, Norihisa; Tochikubo, Kunio

    2004-08-13

    Recombinant cholera toxin B subunit (rCTB) which is produced by Bacillus brevis carrying pNU212-CTB acts as a mucosal adjuvant capable of enhancing host immune responses specific to unrelated, mucosally co-administered vaccine antigens. When mice were administered intranasally with diphtheria-pertussis-tetanus (DPT) combination vaccine consisting of diphtheria toxoid (DTd), tetanus toxoid (TTd), pertussis toxoid (PTd), and formalin-treated filamentous hemagglutinin (fFHA), the presence of rCTB elevated constantly high values of DTd- and TTd-specific serum ELISA IgG antibody titres, and protective levels of diphtheria and tetanus toxin-neutralizing antibodies but the absence of rCTB did not. Moreover, the addition of rCTB protected all mice against tetanic symptoms and deaths. DPT combination vaccine raised high levels of serum anti-PT IgG antibody titres regardless of rCTB and protected mice from Bordetella pertussis challenge. These results suggest that co-administration of rCTB as an adjuvant is necessary for induction of diphtheria and tetanus antitoxin antibodies on the occasion of intranasal administration of DPT combination vaccine.

  19. The effects of adjuvants on autoimmune responses against testicular antigens in mice.

    PubMed

    Musha, Muhetaerjiang; Hirai, Shuichi; Naito, Munekazu; Terayama, Hayato; Qu, Ning; Hatayama, Naoyuki; Itoh, Masahiro

    2013-01-01

    Experimental autoimmune orchitis (EAO) is a model of immunologic male infertility and pathologically characterized by lymphocytic inflammation, which causes breakdown of the testicular immune privilege with spermatogenic disturbance. Generally, murine EAO is induced by immunization with testicular homogenate (TH) from the testes of donor mice + complete Freund's adjuvant (CFA) + Bordetella pertussigens (BP), and it has been considered that treatment with these two adjuvants is required to enhance the immune response against testicular antigens. However, there remains a possibility that CFA and BP may affect autoimmune responses against the testicular antigens without TH. In the present study, we examined this possibility using real-time RT-PCR, Western blotting and immunohistochemical staining. The results demonstrated that immunization with TH in combination with CFA and BP evoked more severe EAO than that with only TH. Real-time RT-PCR analyses revealed that Fas mRNA expression in TH+CFA+BP-induced EAO was significantly higher than that in TH-induced EAO. Interestingly, IL-6 mRNA expression dramatically increased in TH+CFA+BP-induced EAO; however, no apparent change in IL-6 mRNA expression occurred in TH-induced EAO. It was also noted that treatment with CFA and BP alone augmented autoimmune reactions against some testicular autoantigens. These results indicates that these adjuvants are helpful in evoking severe EAO, and treatment with the adjuvants alone can evoke autoimmune reactions against some testicular autoantigens despite the use of no TH.

  20. HIV Envelope Trimer Specific Immune Response Is Influenced by Different Adjuvant Formulations and Heterologous Prime-Boost

    PubMed Central

    Apostólico, Juliana de Souza; Boscardin, Silvia Beatriz; Yamamoto, Márcio Massao; de Oliveira-Filho, Jethe Nunes; Kalil, Jorge; Cunha-Neto, Edecio; Rosa, Daniela Santoro

    2016-01-01

    The development of a preventive vaccine against human immunodeficiency virus (HIV-1) infection is the most efficient method to control the epidemic. The ultimate goal is to develop a vaccine able to induce specific neutralizing, non-neutralizing antibodies and cellular mediated immunity (CMI). Humoral and CMI responses can be directed to glycoproteins that are normally presented as a trimeric spike on the virus surface (gp140). Despite safer, subunit vaccines are normally less immunogenic/effective and need to be delivered together with an adjuvant. The choice of a suitable adjuvant can induce effective humoral and CMI that utterly lead to full protection against disease. In this report, we established a hierarchy of adjuvant potency on humoral and CMI when admixed with the recombinant HIV gp140 trimer. We show that vaccination with gp140 in the presence of different adjuvants can induce high-affinity antibodies, follicular helper T cells and germinal center B cells. The data show that poly (I:C) is the most potent adjuvant to induce specific CMI responses evidenced by IFN-γ production and CD4+/CD8+ T cell proliferation. Furthermore, we demonstrate that combining some adjuvants like MPL plus Alum and MPL plus MDP exert additive effects that impact on the magnitude and quality of humoral responses while mixing MDP with poly (I:C) or with R848 had no impact on total IgG titers but highly impact IgG subclass. In addition, heterologous DNA prime- protein boost yielded higher IgG titers when compare to DNA alone and improved the quality of humoral response when compare to protein immunization as evidenced by IgG1/IgG2a ratio. The results presented in this paper highlight the importance of selecting the correct adjuvant-antigen combination to potentiate desired cells for optimal stimulation. PMID:26727218

  1. In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

    PubMed Central

    Bayry, Jagadeesh; Tchilian, Elma Z.; Davies, Matthew N.; Forbes, Emily K.; Draper, Simon J.; Kaveri, Srini V.; Hill, Adrian V. S.; Kazatchkine, Michel D.; Beverley, Peter C. L.; Flower, Darren R.; Tough, David F.

    2008-01-01

    Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4+CD25+ regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents produced by DC, which are crucial in promoting contact between DC and CCR4+ T cells. Molecules identified by virtual screening and molecular docking as CCR4 antagonists were able to block CCL22- and CCL17-mediated recruitment of human Tregs and Th2 cells. Furthermore, CCR4 antagonists enhanced DC-mediated human CD4+ T cell proliferation in an in vitro immune response model and amplified cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting our hypothesis that CCR4 is a viable target for rational adjuvant design. PMID:18621704

  2. Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials.

    PubMed

    Kreimer, Aimée R; Struyf, Frank; Del Rosario-Raymundo, Maria Rowena; Hildesheim, Allan; Skinner, S Rachel; Wacholder, Sholom; Garland, Suzanne M; Herrero, Rolando; David, Marie-Pierre; Wheeler, Cosette M; González, Paula; Jiménez, Silvia; Lowy, Douglas R; Pinto, Ligia A; Porras, Caroline; Rodriguez, Ana Cecilia; Safaeian, Mahboobeh; Schiffman, Mark; Schiller, John T; Schussler, John; Sherman, Mark E; Bosch, F Xavier; Castellsague, Xavier; Chatterjee, Archana; Chow, Song-Nan; Descamps, Dominique; Diaz-Mitoma, Francisco; Dubin, Gary; Germar, Maria Julieta; Harper, Diane M; Lewis, David J M; Limson, Genara; Naud, Paulo; Peters, Klaus; Poppe, Willy A J; Ramjattan, Brian; Romanowski, Barbara; Salmeron, Jorge; Schwarz, Tino F; Teixeira, Julio C; Tjalma, Wiebren A A

    2015-07-01

    There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received. Summary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and ~the PATRICIA trial (NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase. We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22 327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0% (95% CI 74·7-79·1), two doses was 76·0% (62·0-85·3), and one dose was 85·7% (70·7-93·7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7% (56·0-63·0), two doses was 37·7% (12·4-55·9), and one dose was 36·6% (-5·4 to 62·2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3% (54·2-87·5) and 82·6% (42·3-96·1) for those who received the second

  3. 5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, is responsible for complete Freund's adjuvant-induced thermal hyperalgesia in mice

    PubMed Central

    2011-01-01

    Background The role of serotonin (5-hydroxytrptamine, 5-HT) in the modulation of pain has been widely studied. Previous work led to the hypothesis that 5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, might by itself influence pain thresholds. Results In the present study, we investigated the role of 5-HIAA in inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) into the hind paw of mice. Wild-type mice were compared to mice deficient of the 5-HT transporter (5-HTT-/- mice) using behavioral tests for hyperalgesia and high-performance liquid chromatography (HPLC) to determine tissue levels of 5-HIAA. Wild-type mice reproducibly developed thermal hyperalgesia and paw edema for 5 days after CFA injection. 5-HTT-/- mice treated with CFA had reduced thermal hyperalgesia on day 1 after CFA injection and normal responses to heat thereafter. The 5-HIAA levels in spinal cord and sciatic nerve as measured with HPLC were lower in 5-HTT-/- mice than in wild-type mice after CFA injection. Pretreatment of wild-type mice with intraperitoneal injection of para-chlorophenylalanine (p-CPA), a serotonin synthesis inhibitor, resulted in depletion of the 5-HIAA content in spinal cord and sciatic nerve and decrease in thermal hyperalgesia in CFA injected mice. The application of exogenous 5-HIAA resulted in potentiation of thermal hyperalgesia induced by CFA in 5-HTT-/- mice and in wild-type mice pretreated with p-CPA, but not in wild-type mice without p-CPA pretreatment. Further, methysergide, a broad-spectrum serotonin receptor antagonist, had no effect on 5-HIAA-induced potentiation of thermal hyperalgesia in CFA-treated wild-type mice. Conclusion Taken together, the present results suggest that 5-HIAA plays an important role in modulating peripheral thermal hyperalgesia in CFA induced inflammation, probably via a non-serotonin receptor mechanism. PMID:21447193

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

    PubMed

    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.

  5. Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE2, and MMP-13 expression

    PubMed Central

    Wei, Zhi-feng; Jiao, Xiao-lan; Wang, Ting; Lu, Qian; Xia, Yu-feng; Wang, Zheng-tao; Guo, Qing-long; Chou, Gui-xin; Dai, Yue

    2013-01-01

    Aim: To explore the effects of norisoboldine (NOR), a major isoquinoline alkaloid in Radix Linderae, on joint destruction in rats with adjuvant-induced arthritis (AIA) and its underlying mechanisms. Methods: AIA was induced in adult male SD rats by intradermal injection of Mycobacterium butyricum in Freund's complete adjuvant at the base of the right hind paw and tail. From d 14 after immunization, the rats were orally given NOR (7.5, 15, or 30 mg/kg) or dexamethasone (0.5 mg/kg) daily for 10 consecutive days. Joint destruction was evaluated with radiological scanning and H&E staining. Fibroblast-like synoviocytes (FLS) were prepared from fresh synovial tissues in the AIA rats. The expression of related proteins and mRNAs were detected by ELISA, Western blotting and RT-PCR. Results: In AIA rats, NOR (15 and 30 mg/kg) significantly decreased the swelling of paws and arthritis index scores, and elevated the mean body weight. NOR (30 mg/kg) prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints. However, NOR (15 mg/kg) only suppressed the destruction of bone and cartilage, but did not obviously ameliorate synovial inflammation. NOR (15 and 30 mg/kg) significantly decreased the serum levels of receptor activator of nuclear factor κB ligand (RANKL), IL-6, PGE2, and MMP-13, but not the osteoprotegerin and MMP-1 levels. The mRNA levels of RANKL, IL-6, COX-2, and MMP-13 in synovium were also suppressed. Dexamethasone produced similar effects in AIA rats as NOR did, but without elevating the mean body weight. In the cultured FLS, treatment with NOR (10 and 30 mmol/L) significantly decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 proteins. Furthermore, the treatment selectively prevented the activation of MAPKs, AKT and transcription factor AP-1 component c-Jun, but not the recruitment of TRAF6 or the activation of JAK2/STAT3. Treatment of the cultured FLS with the specific inhibitors of p38, ERK, AKT, and AP-1

  6. A(2A) adenosine receptors are differentially modulated by pharmacological treatments in rheumatoid arthritis patients and their stimulation ameliorates adjuvant-induced arthritis in rats.

    PubMed

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

    2013-01-01

    A(2A) adenosine receptors (ARs) play a key role in the inhibition of the inflammatory process. The purpose of this study was to evaluate the modulation of A(2A)ARs in rheumatoid arthritis (RA) patients after different pharmacological treatments and to investigate the effect of A(2A)AR stimulation in a rat model of arthritis. We investigated A(2A)AR density and functionality in RA progression by using a longitudinal study in RA patients before and after methotrexate (MTX), anti-TNFα agents or rituximab treatments. A(2A)ARs were analyzed by saturation binding assays in lymphocytes from RA patients throughout the 24-month study timeframe. In an adjuvant-induced arthritis model in rats we showed the efficacy of the A(2A)AR agonist, CGS 21680 in comparison with standard therapies by means of paw volume assessment, radiographic and ultrasonographic imaging. Arthritic-associated pain was investigated in mechanical allodynia and thermal hyperalgesia tests. IL-10 release following A(2A)AR stimulation in lymphocytes from RA patients and in serum from arthritic rats was measured. In lymphocytes obtained from RA patients, the A(2A)AR up-regulation was gradually reduced in function of the treatment time and the stimulation of these receptors mediated a significant increase of IL-10 production. In the same cells, CGS 21680 did not affected cell viability and did not produced cytotoxic effects. The A(2A)AR agonist CGS 21680 was highly effective, as suggested by the marked reduction of clinical signs, in rat adjuvant-induced arthritis and associated pain. This study highlighted that A(2A)AR agonists represent a physiological-like therapeutic alternative for RA treatment as suggested by the anti-inflammatory role of A(2A)ARs in lymphocytes from RA patients. The effectiveness of A(2A)AR stimulation in a rat model of arthritis supported the role of A(2A)AR agonists as potential pharmacological treatment for RA.

  7. A phase II study of an investigational tetravalent influenza vaccine formulation combining MF59®: adjuvanted, pre-pandemic, A/H5N1 vaccine and trivalent seasonal influenza vaccine in healthy adults.

    PubMed

    Herbinger, Karl-Heinz; von Sonnenburg, Frank; Nothdurft, Hans Dieter; Perona, Pamela; Borkowski, Astrid; Fragapane, Elena; Nicolay, Uwe; Clemens, Ralf

    2014-01-01

    An investigational tetravalent vaccine combining pre-pandemic, MF59®-adjuvanted A/H5N1 vaccine with non-adjuvanted, trivalent, seasonal influenza vaccine has been developed, which has the potential to be used for pre-pandemic priming and to improve levels of compliance and coverage. It is important to determine whether the safety and immunogenicity of the combination vaccine is equivalent to that of the two separate vaccines when administered concomitantly. Healthy adults (n=601) were randomly assigned to three vaccination groups to receive either: (1) tetravalent vaccine and placebo concomitantly (in separate arms) on Day 1, followed by A/H5N1 vaccine on Day 22; (2) A/H5N1 vaccine and placebo concomitantly on Day 1, followed by tetravalent vaccine on Day 22; or (3) A/H5N1 and seasonal vaccines concomitantly on Day 1, followed by A/H5N1 vaccine on Day 22. Antibody responses were measured using single radial hemolysis (SRH), haemagglutination inhibition (HI), and microneutralization (MN) assays on Days 1, 22, and 43. Solicited adverse reactions were recorded for seven days after vaccination. Spontaneous adverse events were recorded throughout the study. The tetravalent vaccine elicited antibody titers equivalent to those for separate A/H5N1 and seasonal vaccines, and sufficient to meet the European licensure criteria against A/H5N1 and all three seasonal strains. Local and systemic reactions were mainly mild to moderate. No vaccine-related serious adverse events occurred. These findings demonstrate that MF59-adjuvanted A/H5N1 and seasonal influenza vaccines had an acceptable safety profile and could be effectively administered as a tetravalent formulation, supporting the possibility of integrating pre-pandemic priming into seasonal influenza vaccination programs.

  8. An innovative approach to induce cross-protective immunity against porcine reproductive and respiratory syndrome virus in the lungs of pigs through adjuvanted nanotechnology-based vaccination

    PubMed Central

    Binjawadagi, Basavaraj; Dwivedi, Varun; Manickam, Cordelia; Ouyang, Kang; Torrelles, Jordi B; Renukaradhya, Gourapura J

    2014-01-01

    Porcine reproductive and respiratory syndrome (PRRS) is an economically devastating respiratory disease of pigs. The disease is caused by the PRRS virus (PRRSV), an Arterivirus which is a highly mutating RNA virus. Widely used modified live PRRSV vaccines have failed to prevent PRRS outbreaks and reinfections; moreover, safety of the live virus vaccines is questionable. Though poorly immunogenic, inactivated PRRSV vaccine is safe. The PRRSV infects primarily the lung macrophages. Therefore, we attempted to strengthen the immunogenicity of inactivated/killed PRRSV vaccine antigens (KAg), especially in the pig respiratory system, through: 1) entrapping the KAg in biodegradable poly(lactic-co-glycolic acid) nanoparticles (NP-KAg); 2) coupling the NP-KAg with a potent mucosal adjuvant, whole cell lysate of Mycobacterium tuberculosis (M. tb WCL); and 3) delivering the vaccine formulation twice intranasally to growing pigs. We have previously shown that a single dose of NP-KAg partially cleared the challenged heterologous PRRSV. Recently, we reported that NP-KAg coupled with unentrapped M. tb WCL significantly cleared the viremia of challenged heterologous PRRSV. Since PRRSV is primarily a lung disease, our goal in this study was to investigate lung viral load and various immune correlates of protection at the lung mucosal surfaces and its parenchyma in vaccinated heterologous PRRSV-challenged pigs. Our results indicated that out of five different vaccine-adjuvant formulations, the combination of NP-KAg and unentrapped M. tb WCL significantly cleared detectable replicating infective PRRSV with a tenfold reduction in viral RNA load in the lungs, associated with substantially reduced gross and microscopic lung pathology. Immunologically, strong humoral (enhanced virus neutralization titers by high avidity antibodies) and cell-mediated immune responses (augmented population of interferon-γ secreting CD4+ and CD8+ lymphocytes and reduced secretion of immunosuppressive

  9. Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer: The TRAIN-study.

    PubMed

    van Ramshorst, Mette S; van Werkhoven, Erik; Mandjes, Ingrid A M; Schot, Margaret; Wesseling, Jelle; Vrancken Peeters, Marie-Jeanne T F D; Meerum Terwogt, Jetske M; Bos, Monique E M; Oosterkamp, Hendrika M; Rodenhuis, Sjoerd; Linn, Sabine C; Sonke, Gabe S

    2017-03-01

    To determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer. Patients with stage II or III HER2-positive breast cancer received weekly paclitaxel ([P], 70 mg/m(2)), trastuzumab ([T], 2 mg/kg, loading dose 4 mg/kg) and carboplatin ([C], AUC = 3 mg ml(-1) min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy. The primary end-point was pathologic complete response in the surgical resection specimen, defined as the absence of invasive tumour cells in breast and axilla. One hundred and eleven patients were included in the study, and 108 were evaluable for the primary end-point. The pathologic complete response rate was 43% (95% confidence interval [CI]: 33-52). Median follow-up was 52 months, and the 3-year event-free survival was 88% (95% CI: 82-94), and the 3-year overall survival was 92% (95% CI: 88-98). The most common grade 3-4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Less than five percent of patients experienced febrile neutropenia. No symptomatic left ventricular systolic dysfunction was observed during neo-adjuvant treatment. An anthracycline-free neo-adjuvant regimen of weekly paclitaxel, trastuzumab and carboplatin is highly effective in HER2-positive breast cancer with manageable toxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Synthesis of Lymph Node-Targeting Adjuvants.

    PubMed

    Hanson, Melissa C; Irvine, Darrell J

    2017-01-01

    Molecular adjuvants based off of pattern recognition receptor agonists are capable of potently stimulating innate immunity and inducing protective immune responses to subunit antigens. One significant disadvantage to these small molecule adjuvants is their pharmacokinetic profile of entering the blood stream rather than the lymphatics after parental injection. In order to target molecular adjuvants to lymph nodes, we have developed nanoparticle carriers whose size has been optimized to avoid the blood and efficiently drain to lymph nodes (Hanson et al. Vaccine 33:861-8,2015; Hanson et al. J Clin Invest 125:2532-2546, 2015). This chapter describes in detail the materials and procedures necessary to synthesize liposome nanoparticle carriers of either hydrophobic or hydrophilic adjuvants, including synthesis tips, alternative equipment options, and pitfalls to avoid.

  11. Antihypernociceptive and antioxidant effects of Petersianthus macrocarpus stem bark extracts in rats with complete Freund's adjuvant-induced persistent inflammatory pain.

    PubMed

    Bomba, Francis Desire Tatsinkou; Wandji, Bibiane Aimée; Fofié, Christian Kuete; Kamanyi, Albert; Nguelefack, Télesphore Benoit

    2017-03-14

    Background Petersianthus macrocarpus (P. Beauv.) Liben (Lecythidaceae) is a plant used in Cameroonian folk medicine to cure ailments such as inflammation and pain. Previous work showed that aqueous (AEPM) and methanol (MEPM) extracts from the stem bark of P. macrocarpus possess acute analgesic activities. The present study evaluates whether the same extracts could inhibit persistent hyperalgesia induced by complete Freund's adjuvant (CFA) in rats. Methods Inflammatory pain was induced by intraplantar injection of CFA into the left hind paw of Wistar rats. AEPM and MEPM were administered either acutely or chronically by the oral route at the doses of 100 and 200 mg/kg/day. The mechanical hyperalgesia was tested using an analgesimeter, while the locomotion activity at the end of experiment was evaluated with an open-field device. Nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD) contents were assayed in the brain and spinal cord of rats subjected to 14 days chronic treatment. Results AEPM and MEPM at both doses significantly (p<0.001) inhibited the acute and chronic mechanical hyperalgesia induced by CFA. Although not significant, both extracts increased the mobility of CFA-injected animals. AEPM significantly (p<0.01) reduced the level of nitrate at 100 mg/kg, MDA at 200 mg/kg and significantly (p<0.05) increased the SOD in the spinal cord. MEPM significantly increased the SOD content and reduced the MDA concentration in the brain but had no effect on the nitrate. Conclusions AEPM and MEPM exhibit acute and chronic antihyperalgesic activities. In addition, both extracts possess antioxidant properties that might strengthen their chronic antihyperalgesic effects.

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

    PubMed

    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.

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

    PubMed

    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.

  14. ω-3 fatty acids as an adjuvant therapy ameliorates methotrexate-induced hepatotoxicity in children and adolescents with acute lymphoblastic leukemia: A randomized placebo-controlled study.

    PubMed

    Elbarbary, Nancy Samir; Ismail, Eman Abdel Rahman; Farahat, Reham Kamel; El-Hamamsy, Manal

    2016-01-01

    Methotrexate (MTX)-induced hepatotoxicity is a significant clinical problem that may affect overall prognosis and disease outcome. Oxidative stress is a key player in its pathogenesis. The aim of this study was to investigate the role of ω-3 fatty acids as an adjuvant therapy in children and adolescents with acute lymphoblastic leukemia (ALL) during the maintenance phase of chemotherapy and the effect of ω-3 on MTX-induced hepatotoxicity. This randomized, double-blind, placebo-controlled trial included 70 patients with ALL who were