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Sample records for adjuvant induced arthritic

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. Anti-tumor necrosis factor agent PEG-sTNFRI improves the growth hormone/insulin-like growth factor-I system in adjuvant-induced arthritic rats.

    PubMed

    Granado, Miriam; Priego, Teresa; Martín, Ana Isabel; Vara, Elena; López-Calderón, Asunción; Angeles Villanúa, María

    2006-04-24

    Adjuvant-induced arthritis is associated with body weight loss and decreased pituitary growth hormone (GH) and hepatic insulin-like growth factor-I (IGF-I) synthesis. Cytokines as tumor necrosis factor (TNF) mediate wasting associated with chronic inflammation. The aim of this study was to analyse whether the inhibition of TNF is able to revert the decrease in the body weight and the GH/IGF-I axis in arthritic rats. Male Wistar rats were injected with Freund's adjuvant, and 15 days later arthritic and control rats were daily injected with polyethylene glycol linked to soluble TNF receptor p55 (PEG-sTNFRI) (1 mg/kg, s.c.) or saline for 8 days. There was a significant decrease in pituitary GH mRNA (P<0.05), hepatic IGF-I mRNA (P<0.01) and serum concentrations of IGF-I (P<0.01) in arthritic rats. The 8-day administration of PEG-sTNFRI resulted in an increase in food intake (P<0.05) and body weight gain (P<0.01) in arthritic but not in control rats. There was an increase in pituitary GH mRNA after PEG-sTNFRI treatment both in control and in arthritic rats. There was a significant increase in IGF-I serum concentrations (P<0.05) and hepatic IGF-I mRNA expression (P<0.05) in control rats treated with PEG-sTNFRI, whereas the effect of this anti-TNF agent in arthritic rats was only statistically significant in hepatic IGF-I mRNA expression (P<0.05). These data suggest that TNF seems to be involved in the decrease in GH and IGF-I synthesis in arthritic rats.

  8. 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

  9. 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

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

    PubMed Central

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

    2015-01-01

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

  11. 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.

  12. 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

  13. Majoon ushba, a polyherbal compound, suppresses pro-inflammatory mediators and RANKL expression via modulating NFкB and MAPKs signaling pathways in fibroblast-like synoviocytes from adjuvant-induced arthritic rats.

    PubMed

    Ganesan, Ramamoorthi; Doss, Hari Madhuri; Rasool, Mahaboobkhan

    2016-08-01

    Fibroblast-like synoviocytes (FLS) are inhabitant mesenchymal cells of synovial joints and have been recognized to play an imperative role in the immunopathogenesis of rheumatoid arthritis (RA). Blocking these pathological roles of FLS provides a potentially important therapeutic strategy for the treatment for RA. A recent study had confirmed that majoon ushba (MU), a polyherbal unani compound, possesses anti-arthritic effects in in vivo. Toward this direction, an effort has been made to understand the effect of MU on FLS derived from adjuvant-induced arthritis (AIA) rats. Here, we observed that MU administration (100-300 µg/ml) significantly inhibited the expression and phosphorylation of NFкB-p65 protein similar to that of the Bay 11-7082 (NFкB inhibitor) in NFкB signaling pathway and suppressed the protein expression of ERK1/2 and JNK1/2 in MAPKs signaling pathway in AIA-FLS. In addition, the protein expression of TNF-α, IL-17, RANKL, and iNOS was also found reduced. MU treatment significantly inhibited the mRNA expression of pro-inflammatory mediators (TNF-α, IL-1β, IL-6, MCP-1, IL-17, iNOS, and COX-2), transcription factors (NFкB-p65 and AP-1), and RANKL and attenuated the overproduction of TNF-α, IL-1β, IL-6, and MCP-1 (ELISA) in AIA-FLS. Furthermore, MU treatment significantly inhibited the level of lipid peroxidation, lysosomal enzymes release, and glycoproteins and increased antioxidant status (superoxide dismutase and catalase) in AIA-FLS. In conclusion, the results of this study provide evidence that MU possesses anti-inflammatory effect against AIA-FLS through the decrease in pro-inflammatory mediators expression by suppressing NFкB and MAPKs signaling pathways.

  14. Anti-Arthritic Activity of Schistosoma mansoni and Trichinella spiralis Derived-Antigens in Adjuvant Arthritis in Rats: Role of FOXP3+ Treg Cells

    PubMed Central

    Eissa, Maha M.; Ghazy, Amany A.; El azzouni, Mervat Z.; Boulos, Laila M.; Younis, Layla K.

    2016-01-01

    A growing body of evidence supports the concept of helminths therapy in a variety of autoimmune diseases. Here, we aimed to investigate the protective effects of autoclaved Schistosoma mansoni antigen (ASMA) and Trichinella spiralis antigen (ATSA) on the clinical and immunopathological features of rheumatoid arthritis (RA). Adjuvant arthritis was induced by subcutaneous and intradermal injections of complete Freund’s adjuvant into the plantar surface of the right hind paw and the root of the tail, respectively. Rats were randomly assigned to serve as normal control, untreated arthritis, ASMA or ATSA-treated arthritis groups. Antigens were given by intradermal injection in two doses, two weeks apart. The development, progression of arthritic features, and the impact on animals’ gait and body weight were followed up for 4 weeks. The associated changes in serum cytokines (IL-17, IFN-γ and IL-10), joints’ histopathology and immunohistochemistry of Foxp3+ T regulatory cells (Tregs) were evaluated at the end of the study. Treatment with either ASMA or ATSA attenuated the progression of clinical features of polyarthritis, improved gait and body weight gain, reduced the elevated serum IL-17 and further increased both IFN-γ and IL-10. Histopathologically, this was associated with a remarkable regression of paws’ inflammation that was limited only to the subcutaneous tissue, and a significant increase in the number of Foxp 3+ cells versus the untreated arthritis group. In conclusion, both Schistosoma mansoni and Trichinella spiralis derived antigens exerted protective effect against adjuvant arthritis with better effect achieved by ASMA treatment. This anti-arthritic activity is attributed to upregulation of the Foxp3+ Tregs, with subsequent favorable modulation of both pro- and anti-inflammatory cytokines. The use of autoclaved parasitic antigens excludes the deleterious effects of imposing helminthic infection by using live parasites, which may pave the way to a

  15. 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

  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. Arthritic disease is more severe in older rats in a kaolin/carrageenan-induced arthritis model.

    PubMed

    Kim, Kyoung Soo; Kim, Myung-Hwan; Yeom, Mijung; Choi, Hyun Mi; Yang, Hyung-In; Yoo, Myung Chul; Hahm, Dae-Hyun

    2012-12-01

    This study examined in an arthritis animal model whether elderly onset rheumatoid arthritis (EORA) is a more severe disease than younger onset rheumatoid arthritis. Arthritis was induced by injecting 5% kaolin/carrageenan into the left tibiotarsal ankles of 18-month-old and 4-week-old rats. Various parameters were measured to evaluate the arthritic progression of kaolin/carrageenan-induced arthritis in the rats. Immunohistochemical staining of arthritic joints was performed to determine the degree of inflammation in old and young rats. Measurements of ankle volume and thickness, arthritic index, number of squeaks, and the paw pressure test showed the 18-month-old rats had more severe disease than the young rats in a kaolin/carrageenan-induced arthritis model. The degree of inflammation and MMP-1 expression of arthritic joints in old rats was significantly higher than that of young rats based on histological evaluation with hematoxylin and eosin (H&E) staining and immunochemistry. More severe disease symptoms were found in old rats with EORA, but the molecular mechanisms still remain to be elucidated. Understanding the molecular mechanisms will be helpful to develop clinical protocols to efficiently treat patients with EORA, which is difficult to control with current protocols.

  18. 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.

  19. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis.

    PubMed

    Malfait, A M; Gallily, R; Sumariwalla, P F; Malik, A S; Andreakos, E; Mechoulam, R; Feldmann, M

    2000-08-15

    The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant. The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg/kg per day i.p. or 25 mg/kg per day orally. Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-gamma production, as well as a decreased release of tumor necrosis factor by knee synovial cells. In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes. It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57/BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.

  20. Grape seed proanthocyanidin extract has potent anti-arthritic effects on collagen-induced arthritis by modifying the T cell balance.

    PubMed

    Ahmad, Sheikh Fayaz; Zoheir, Khairy M A; Abdel-Hamied, Hala E; Ashour, Abdelkader E; Bakheet, Saleh A; Attia, Sabry M; Abd-Allah, Adel R A

    2013-09-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterised by chronic inflammation of the synovial joints, joint malformations, and disability. The continuous use of conventional anti-inflammatory drugs is associated with severe adverse effects. Grape seed proanthocyanidin extract (GSPE) is considered to have protective effects against several diseases. In this study based on the mouse adjuvant-induced-arthritis (AIA) model, we examined the effects of GSPE on the key mediators of arthritic inflammation, namely T cell subsets, glucocorticoid-induced tumour necrosis factor receptor (GITR) expressing cells, CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells, Th17 cells, Th1/Th2 cytokines, and inflammatory mediator gene expression. We treated BALB/c mice with 25, 50, or 100 mg/kg GSPE or saline daily (14 days) per orally (p.o.) at the onset of AIA. At the peak phase of AIA (day 14), the heparinised whole blood and ankle joints of all groups were collected and tested. GSPE-treated mice showed a substantial reduction in the levels of T cell subsets, GITR-expressing cells, and Th1 cytokines as well as the inflammatory mediators (MCP-1, MIP-2, and ICAM-1) that induce them compared with the vehicle-treated (saline) and arthritic mice. However, GSPE significantly upregulated the number of Tregs and Th2 cytokine producing cell number or it also induced Th17/Treg rebalance and orchestrated various pro-inflammatory and anti-inflammatory cytokines and the gene expression of their mediators that mediate cellular infiltration into the joints. This might, contribute to its anti-arthritic activity. Our results suggest that p.o. treatment with GSPE attenuated AIA in mice might offer a promising alternative/adjunct treatment for RA.

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. Chrysin alleviates testicular dysfunction in adjuvant arthritic rats via suppression of inflammation and apoptosis: Comparison with celecoxib

    SciTech Connect

    Darwish, Hebatallah A.; Arab, Hany H.; Abdelsalam, Rania M.

    2014-09-01

    Long standing rheumatoid arthritis (RA) is associated with testicular dysfunction and subfertility. Few studies have addressed the pathogenesis of testicular injury in RA and its modulation by effective agents. Thus, the current study aimed at evaluating the effects of two testosterone boosting agents; chrysin, a natural flavone and celecoxib, a selective COX-2 inhibitor, in testicular impairment in rats with adjuvant arthritis, an experimental model of RA. Chrysin (25 and 50 mg/kg) and celecoxib (5 mg/kg) were orally administered to Wistar rats once daily for 21 days starting 1 h before arthritis induction. Chrysin suppressed paw edema with comparable efficacy to celecoxib. More important, chrysin, dose-dependently and celecoxib attenuated the testicular injury via reversing lowered gonadosomatic index and histopathologic alterations with preservation of spermatogenesis. Both agents upregulated steroidogenic acute regulatory (StAR) mRNA expression and serum testosterone with concomitant restoration of LH and FSH. Furthermore, they suppressed inflammation via abrogation of myeloperoxidase, TNF-α and protein expression of COX-2 and iNOS besides elevation of IL-10. Alleviation of the testicular impairment was accompanied with suppression of oxidative stress via lowering testicular lipid peroxides and nitric oxide. With respect to apoptosis, both agents downregulated FasL mRNA expression and caspase-3 activity in favor of cell survival. For the first time, these findings highlight the protective effects of chrysin and celecoxib against testicular dysfunction in experimental RA which were mediated via boosting testosterone in addition to attenuation of testicular inflammation, oxidative stress and apoptosis. Generally, the 50 mg/kg dose of chrysin exerted comparable protective actions to celecoxib. - Highlights: • Chrysin and celecoxib alleviated testicular suppression in adjuvant arthritis. • They attenuated histopathological damage and preserved spermatogenesis

  9. Anti-arthritic activity of various extracts of Sida rhombifolia aerial parts.

    PubMed

    Gupta, S R; Nirmal, S A; Patil, R Y; Asane, G S

    2009-01-01

    Aerial parts of the plant Sida rhombifolia Linn. (Malvaceae) were extracted successively to produce various extracts. These extracts were screened for various parameters of anti-arthritic activity, such as adjuvant-induced arthritis, motor performance, mean distance travelled, and histopathological study. Results showed that the polar constituents (ethanol and aqueous extracts) of the plant S. rhombifolia were useful in the treatment of arthritis.

  10. Anti arthritic and anti inflammatory activity of a cytotoxic protein NN-32 from Indian spectacle cobra (Naja naja) venom in male albino rats.

    PubMed

    Gomes, Antony; Datta, Poulami; Das, Tanaya; Biswas, Ajoy Kumar; Gomes, Aparna

    2014-11-01

    The anti arthritic and anti inflammatory activity of NN-32, a cytotoxic protein from Indian spectacle cobra snake (Naja naja) venom has been studied in Freund's complete adjuvant (FCA) induced arthritis and carrageenan induced anti inflammatory model. NN-32 treatment showed significant decrease in physical and urinary parameters, serum enzymes, serum cytokines levels as compared to arthritic control group of rats. NN-32 treatment recovered carrageenan induced inflammation as compared to control group of rats. The findings showed that the cytotoxic protein NN-32 shares anti arthritic and anti inflammatory activity and thus NN-32 may target complex pathophysiological processes like cancer- arthritis-inflammation.

  11. 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.

  12. 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.

  13. PTHrP Overexpression Partially Inhibits a Mechanical Strain-Induced Arthritic Phenotype in Chondrocytes

    PubMed Central

    Wang, Dean; Taboas, Juan M.; Tuan, Rocky S.

    2010-01-01

    Objective Cell-based tissue engineering strategies are currently in clinical use and continue to be developed at a rapid pace for the repair of cartilage defects. Regardless of the repair methodology, chondrocytes within newly regenerated cartilage remain susceptible to the abnormal inflammatory and mechanical environments that underlie osteoarthritic disease, likely compromising the implant’s integration, function, and longevity. The present study investigates the use of parathyroid hormone-related peptide (PTHrP) overexpression for chondroprotection. Design Bovine articular chondrocytes were transfected with human PTHrP (hPTHrP) constructs (1-141 or 1-173) and subjected to injurious cyclic tensile strain (CTS; 0.5 Hz and 16% elongation) for 48 hours. mRNA expression of matrix remodeling, inflammatory signaling, hypertrophic, and apoptotic genes were examined with real-time reverse transcription polymerase chain reaction. Nitric oxide (NO) and prostaglandin E2 (PGE2) production were measured using the Griess assay and enzyme immunoassay, respectively. Results CTS induced an arthritic phenotype in articular chondrocytes as indicated by increased gene expression of collagenases and aggrecanases and increased production of NO and PGE2. Additionally, CTS increased collagen type X (Col10a1) mRNA expression, whereas overexpression of either hPTHrP isoform inhibited CTS-induced Col10a1 gene expression. However, hPTHrP 1-141 augmented CTS-induced NO and PGE2 production, and neither hPTHrP isoform had any significant effect on apoptotic genes. Conclusions Our results suggest that chondrocytes overexpressing PTHrP resist mechanical strain-induced hypertrophic-like changes. Therapeutic PTHrP gene transfer may be considered for chondroprotection applications in newly regenerated cartilage. PMID:21087676

  14. Pharmacokinetics, pharmacodynamics, and toxicities of methotrexate in healthy and collagen-induced arthritic rats

    PubMed Central

    Liu, Dong-Yang; Lon, Hoi-Kei; Wang, Yan-Lin; DuBois, Debra C.; Almon, Richard R.; Jusko, William J.

    2013-01-01

    Methotrexate (MTX) is an anchor drug used to treat rheumatoid arthritis (RA), but responsiveness is variable in effectiveness and toxicity. Methotrexate and its polyglutamate conjugates (MTXPGn) in red blood cells (RBC) have been associated with patient response. In the current study, 13 collagen-induced arthritic (CIA) rats and 12 healthy rats were given subcutaneous doses of either saline or 0.3 or 1.5 mg/kg per 2 days of MTX from day 21 to 43 post-induction. Blood samples were obtained at various times to measure MTX in plasma, and MTX and MTXPGn in RBC. Effects on disease progression were indicated by body weight and paw size. After multiple-doses, RBC MTX reached steady-state (82.4 nM) within 4 days. The MTXPG2 and MTXPG3 in RBC kept increasing until the end of the study attaining 12.5 and 17.7 nM. Significant weight loss was observed after dosing of 1.5 mg/kg/2 days, whereas moderate effectiveness was observed after dosing of 0.3 mg/kg/2 days. A pharmacokinetic/ pharmacodynamic/disease (PK/PD/DIS) model with indirect mechanisms and transduction components incorporating plasma MTX, RBC MTX, and RBC MTXPGn concentrations, and paw size was developed using naïve data pooling and ADAPT 5. The PK/PD in CIA rats dosed at 0.3 mg/kg/2 days were captured well by our proposed model. MTX showed modest (Imaxd = 0.16) but sensitive (IC50d = 0.712 nM) effectiveness on paw edema. The higher dose produced toxicity. The proposed model offers improved understanding of MTX effects on rheumatoid arthritis. PMID:23456770

  15. 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

  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. Anti-rheumatoid arthritic effects of Saussurea involucrata on type II collagen-induced arthritis in rats.

    PubMed

    Xu, Meihong; Guo, Qianying; Wang, Shuangjia; Wang, Na; Wei, Liren; Wang, Junbo

    2016-02-01

    Saussurea involucrata (SI) has long been used under the herbal name "snow lotus" for treatment of inflammation and pain-related diseases in traditional Chinese medicine. The present study aimed to evaluate the pharmacological effects of SI on collagen II (CII)-induced arthritis in rats. Rats with collagen II (CII)-induced arthritis were orally administered SI (420 mg kg(-1)) for 40 consecutive days. Histopathological examination indicated that SI alleviates infiltration of inflammatory cells and synovial hyperplasia and slows joint destruction. SI intervention reduced the serum levels of RF, COMP, CRP and anti-CII IgG. Results also showed that SI is a potential therapeutic agent for alleviating the severity of the disease based on the reduced arthritic index. It was concluded that SI can ameliorate inflammation and joint destruction in CIA rats.

  19. 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

  20. 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

  1. 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

  2. Protective effect of curcumin on experimentally induced arthritic rats: detailed histopathological study of the joints and white blood cell count.

    PubMed

    Kamarudin, Taty Anna; Othman, Faizah; Mohd Ramli, Elvy Suhana; Md Isa, Nurismah; Das, Srijit

    2012-01-01

    Curcuma longa (turmeric) rhizomes contains curcumin, an active compound which possesses anti-inflammatory effects. Collagen-induced arthritis (CIA) is an accepted experimental animal model of rheumatoid arthritis. The present study aimed to observe the histological changes in the joints of experimental arthritic rats treated with curcumin. Twenty four male Sprague-Dawley (approximately 7 weeks-old) rats were randomly divided into four groups. Three groups were immunized with 150 µg collagen. All rats with established CIA, with arthritis scores exceeding 1, were orally treated with betamethasone (0.5 mg/ml/kg body weight), curcumin (110 mg/ml/kg body weight) or olive oil (1.0 ml/kg body weight) daily, for two weeks. One remaining group was kept as normal control. Treatment with 110 mg/ml/kg curcumin showed significant mean differences in the average white blood cell (WBC) count (p<0.05), cell infiltration, bone and cartilage erosion scores (p<0.05) compared to the olive oil treated group. Pannus formation scores showed that curcumin supplementation successfully suppressed the pannus formation process that occurred in the articular cartilage of the CIA joints. The mean difference for histological scores for the curcumin group was insignificant compared to the betamethasone treated group. It is concluded that supplementation of curcumin has protective effect on the histopathological and degenerative changes in the joints of CIA rats which was at par with betamethasone.

  3. Fenofibrate administration to arthritic rats increases adiponectin and leptin and prevents oxidative muscle wasting

    PubMed Central

    Castillero, Estíbaliz; Martín, Ana Isabel; Nieto-Bona, Maria Paz; Fernández-Galaz, Carmen; López-Menduiña, María; Villanúa, María Ángeles; López-Calderón, Asunción

    2012-01-01

    Chronic inflammation induces skeletal muscle wasting and cachexia. In arthritic rats, fenofibrate, a peroxisome proliferator-activated receptor α (PPARα (PPARA)) agonist, reduces wasting of gastrocnemius, a predominantly glycolytic muscle, by decreasing atrogenes and myostatin. Considering that fenofibrate increases fatty acid oxidation, the aim of this study was to elucidate whether fenofibrate is able to prevent the effect of arthritis on serum adipokines and on soleus, a type I muscle in which oxidative metabolism is the dominant source of energy. Arthritis was induced by injection of Freund's adjuvant. Four days after the injection, control and arthritic rats were gavaged daily with fenofibrate (300 mg/kg bw) or vehicle over 12 days. Arthritis decreased serum leptin, adiponectin, and insulin (P<0.01) but not resistin levels. In arthritic rats, fenofibrate administration increased serum concentrations of leptin and adiponectin. Arthritis decreased soleus weight, cross-sectional area, fiber size, and its Ppar α mRNA expression. In arthritic rats, fenofibrate increased soleus weight, fiber size, and Ppar α expression and prevented the increase in Murf1 mRNA. Fenofibrate decreased myostatin, whereas it increased MyoD (Myod1) and myogenin expressions in the soleus of control and arthritic rats. These data suggest that in oxidative muscle, fenofibrate treatment is able to prevent arthritis-induced muscle wasting by decreasing Murf1 and myostatin expression and also by increasing the myogenic regulatory factors, MyoD and myogenin. Taking into account the beneficial action of adiponectin on muscle wasting and the correlation between adiponectin and soleus mass, part of the anticachectic action of fenofibrate may be mediated through stimulation of adiponectin secretion. PMID:23781298

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

    PubMed Central

    Gupta, Mradu; Sasmal, Saumyakanti; Mukherjee, Arup

    2014-01-01

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

  5. Anti-rheumatoid arthritic activity of flavonoids from Daphne genkwa.

    PubMed

    Jiang, Cui-Ping; He, Xin; Yang, Xiao-Lin; Zhang, Su-Li; Li, Hui; Song, Zi-Jing; Zhang, Chun-Feng; Yang, Zhong-Lin; Li, Ping; Wang, Chong-Zhi; Yuan, Chun-Su

    2014-05-15

    The aim of the study was to investigate the anti-rheumatoid arthritic activity of four flavonoids from Daphne genkwa (FFD) in vivo and in vitro. Flavonoids of D. genkwa were extracted by refluxing with ethanol and purified by polyamide resin. An in vivo carrageenan-induced paw edema model, tampon-granuloma model and Freund's complete adjuvant (FCA)-induced arthritis mouse model were used to evaluate the anti-rheumatoid arthritic activities of FFD. Moreover, nitric oxide (NO) release and neutral red uptake (NRU) in lipopolysaccharide (LPS)-induced murine macrophage RAW264.7 cells were used to evaluate the anti-inflammatory effect in vitro. In addition, antioxidant effect of FFD was determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. A high dose of FFD significantly reduced the degree of acute inflammatory paw edema in mice as a response to carrageenan administration (p<0.01). FFD displayed a dose-dependent inhibition of granuloma formation in mice (p<0.05). FFD also inhibited chronic inflammation in adjuvant-induced arthritis rats when administered orally at the dose of 50mg/kg/day (p<0.001). In addition, FFD suppressed the production of NO and exhibited immunoregulatory function in LPS-activated RAW264.7 cells in a dose-related manner. Simultaneously, FFD revealed conspicuous antioxidant activity with IC50 values of 18.20μg/ml. FFD possesses significant anti-inflammatory and antioxidant activity, which could be a potential therapeutic agent for chronic inflammatory disorders such as rheumatoid arthritis.

  6. Anti-arthritic activity of Fu-Fang-Lu-Jiao-Shuang on collagen-induced arthritis in Balb/c mice and its underlying mechanisms

    PubMed Central

    Wang, Yanyan; Sun, Weiguang; Chen, Laxia; Xu, Xin; Wu, Yunxia; Zhang, Jinwen; Zhang, Yonghui

    2015-01-01

    Background: Rheumatoid arthritis (RA) is a common, autoimmune disorder characterized by progressive multiple joint destruction, deformity, disability and premature death in most patients. Fu-Fang-Lu-Jiao-Shuang (FFLJS) is an effective traditional Chinese medicine, which has long been used clinically to treat RA patients. Objective: The objective of this study is aimed to evaluate the anti-rheumatic effects of FFLJS on collagen induced arthritis (CIA) model, as well as the underlying mechanisms, which have not previously been explored. Materials and Methods: CIA was induced by immunization with type II collagen (CII) in male Balb/c mice. The mice in the onset of arthritis were treated daily with FFLJS (125 or 500 mg/kg) or 1% carboxymethyl cellulose-Na for 28 days. Paw thickness and arthritic score were evaluated to confirm the anti-arthritic effect of FFLJS on CIA in mice. Levels of anti-CII antibody, proinflammatory cytokines interleukin-1 (IL-1) β, IL-17, and tumor necrosis factor-α (TNF-α) as well as prostaglandin E-2 (PGE-2) in serum and histological changes in the ankle joint were also analyzed. In addition, expressions of matrix metalloproteinases-1 (MMP-1), MMP-3 and tissue inhibitors of matrix metalloproteases-1 (TIMP-1) in synovial tissue were also detected to further study the molecular mechanism of the anti-arthritic effects of FFLJS. Results: During therapeutic treatment, FFLJS significantly reduced paw thickness and arthritic score in CIA mice, decreased the amounts of TNF-α, IL-1 β, IL-17, PGE-2 and anti-CII antibody in serum. In addition, FFLJS treatment could prevent the bone destruction by reducing the expression of MMP-1 and MMP-3, increasing the expression of TIMP-1 in synovial tissue of CIA mice. Conclusion: These findings offer the convincing evidence for the first time that the anti-rheumatic effects of FFLJS might be related to down-regulation of TNF-α, IL-1 β, IL-17 and PGE-2 levels for acute arthritis, and regulation of MMP-1, MMP-3

  7. Anti-arthritic active fraction of Capparis spinosa L. fruits and its chemical constituents.

    PubMed

    Feng, Xiaolu; Lu, Jincai; Xin, Hailiang; Zhang, Lei; Wang, Yuliang; Tang, Kexuan

    2011-03-01

    The aim of this study was to ascertain the anti-arthritic active fraction of Capparis spinosa L. (Capparidaceae) fruits and its chemical constituents. The adjuvant arthritic rat model was developed to evaluate the anti-arthritic effects of different fractions of ethanol extraction from C. spinosa L. The fraction eluted by ethanol-water (50:50, v/v) had the most significant anti-arthritic activity. The chemical constituents of this fraction were therefore studied; seven known compounds were isolated and identified as: P-hydroxy benzoic acid; 5-(hydroxymethyl) furfural; bis(5-formylfurfuryl) ether; daucosterol; α-D-fructofuranosides methyl; uracil; and stachydrine.

  8. In vitro and in vivo evaluation of anti-arthritic, antioxidant efficacy of fucoidan from Undaria pinnatifida (Harvey) Suringar.

    PubMed

    Phull, Abdul-Rehman; Majid, Muhammad; Haq, Ihsan-Ul; Khan, Muhammad Rashid; Kim, Song Ja

    2017-04-01

    Seaweed and their constituents have been traditionally employed for the management of various human pathologic conditions such as edema, urinary disorders and inflammatory anomalies. The current study was performed to investigate the antioxidant and anti-arthritic effects of fucoidan from Undaria pinnatifida. A noteworthy in vitro antioxidant potential at 500μg/ml in 2, 2-diphenyl-1-picrylhydrazyl scavenging assay (80% inhibition), nitrogen oxide inhibition assay (71.83%), hydroxyl scavenging assay (71.92%), iron chelating assay (73.55%) and a substantial ascorbic acid equivalent reducing power (399.35μg/mg ascorbic acid equivalent) and total antioxidant capacity (402.29μg/mg AAE) suggested fucoidan a good antioxidant agent. Down regulation of COX-2 expression in rabbit articular chondrocytes in a dose (0-100μg) and time (0-48h) dependent manner, unveiled its in vitro anti-inflammatory significance. In vivo carrageenan induced inflammatory rat model demonstrated a 68.19% inhibition of inflammation whereas an inflammation inhibition potential of 79.38% was recorded in anti-arthritic complete Freund's adjuvant-induced arthritic rat model. A substantial ameliorating effect on altered hematological and biochemical parameters in arthritic rats was also observed. Therefore, findings of the present study prospects fucoidan as a potential antioxidant that can effectively abrogate oxidative stress, edema and arthritis-mediated inflammation and mechanistic studies are recommended for observed activities.

  9. Anti-inflammatory and Antioxidant Actions of Copaiba Oil Are Related to Liver Cell Modifications in Arthritic Rats.

    PubMed

    de Castro Ghizoni, Cristiane V; Ames, Ana P Arssufi; Lameira, Osmar A; Bersani Amado, Ciomar A; de Sá Nakanishi, Anacharis B; Bracht, Lívia; Natali, Maria R Marçal; Peralta, Rosane M; Bracht, Adelar; Comar, Jurandir F

    2017-03-21

    The present study investigated the action of copaiba oil (Copaifera reticulata) on the systemic inflammation, oxidative status and liver cell metabolism of rats with adjuvant-induced arthritis. The later is an experimental autoimmune pathology that shares many features with the human rheumatoid arthritis. Holtzman rats were distributed into the following groups: control (healthy) rats; control rats treated with copaiba oil at the doses of 0.58 and 1.15 g · Kg(-1) , arthritic rats, and arthritic rats treated with copaiba oil (0.58 and 1.15 g · Kg(-1) ). The oil was administrated orally once a day during 18 days after arthritis induction. Both doses of copaiba oil improved the paw edema and the dose of 0.58 mg · Kg(-1) improved the swollen adrenals and lymph nodes besides decreasing the plasmatic myeloperoxidase activity (-30%) of arthritic rats. Copaiba oil (1.15 g · Kg(-1) ) abolished the increases of protein carbonyl groups and reactive oxygen species in the liver and both doses increased the liver GSH content and the catalase activity in arthritic rats. Copaiba oil (1.15 g · Kg(-1) ) decreased glycolysis (-65%), glycogenolysis (-58%) and gluconeogenesis (-30%) in the liver of arthritic animals. However, gluconeogenesis was also diminished by the treatment of control rats, which presented lower body weight gain (-45%) and diminished number of hepatocytes per liver area (-20%) associated to higher liver weight (+29%) and increased hepatocyte area (+13%). The results reveal that copaiba oil presented systemic anti-inflammatory and antioxidant actions in arthritic rats. These beneficial effects, however, were counterbalanced by harmful modifications in the liver cell metabolism and morphology of healthy control rats. This article is protected by copyright. All rights reserved.

  10. Anti-inflammatory effect of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) in arthritic rats.

    PubMed

    Granado, Miriam; Priego, Teresa; Martín, Ana I; Villanúa, M Angeles; López-Calderón, Asunción

    2005-03-01

    Chronic arthritis induces hypermetabolism and cachexia. Ghrelin is a gastrointestinal hormone that has been proposed as a treatment to prevent cachexia. The aim of this work was to examine the effect of administration of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) to arthritic rats. Male Wistar rats were injected with Freund's adjuvant, and 15 days later arthritic and control rats were daily injected with GHRP-2 (100 microg/kg) or with saline for 8 days. Arthritis induced an increase in serum ghrelin (P < 0.01) and a decrease in serum concentrations of leptin (P < 0.01), whereas GHRP-2 administration increased serum concentrations of leptin. GHRP-2 increased food intake in control rats but not in arthritic rats. However, in arthritic rats GHRP-2 administration ameliorated the external symptoms of arthritis, as it decreased the arthritis score (10.4 +/- 0.8 vs. 13.42 +/- 0.47, P < 0.01) and the paw volume. In addition, circulating IL-6 and nitrites/nitrates were increased by arthritis, and GHRP-2 treatment decreased the serum IL-6 levels (P < 0.01). To elucidate whether GHRP-2 is able to modulate IL-6 release directly on immune cells, peritoneal macrophage cultures were incubated with GHRP-2 or ghrelin, the endogenous ligand of the growth hormone (GH) secretagogue receptor. Both GHRP-2 (10(-7) M) and ghrelin (10(-7) M) prevented endotoxin-induced IL-6 and decreased nitrite/nitrate release from peritoneal macrophages in vitro. These data suggest that GHRP-2 administration has an anti-inflammatory effect in arthritic rats that seems to be mediated by ghrelin receptors directly on immune cells.

  11. 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

  12. Vascular endothelial dysfunction associated with elevated serum homocysteine levels in rat adjuvant arthritis: effect of vitamin E administration.

    PubMed

    Can, Cenk; Cinar, Mehtap G; Koşay, Sezen; Evinç, Akgün

    2002-06-14

    We aimed to study the alterations in serum homocysteine levels and endothelium-dependent and -independent vascular relaxant responses in adjuvant-induced arthritis of the rat and to determine the effects of vitamin E administration on these changes. Arthritis was induced by a single intradermal injection of Freund's complete adjuvant into the paw. 26 days after the induction of arthritis, serum homocysteine levels and relaxant responses to acetylcholine and sodiumnitroprusside in thoracic aortas were evaluated. The relaxant responses to acetylcholine were decreased in aortas from arthritic rats, whereas the responses to sodiumnitroprusside were not significantly different when compared to the aortas from control rats. A significant increase was observed in serum homocysteine levels of the arthritic rats in comparison to those of controls. Vitamin E administration (100 mg/kg/day, i.m. for 26 days) to arthritic rats resulted in a significant increase in endothelium-dependent aortic responses to acetylcholine and a significant decrease in serum homocysteine levels with respect to the non-treated arthritic rats. However, in healthy rats, vitamin E treatment significantly decreased the acetylcholine-induced relaxant responses. We conclude that adjuvant-induced arthritis in the rat is associated with increased serum homocysteine levels and this is accompanied by a reduction in endothelium-dependent vascular responses in the thoracic aortas. Vitamin E treatment leads to normalization of the increased serum homocysteine levels and improves the endothelium-dependent relaxant responses in this experimental model.

  13. 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.

  14. Anti-arthritic activity of a classical Ayurvedic formulation Vatari Guggulu in rats.

    PubMed

    Patel, Madhavi G; Pundarikakshudu, Kilambi

    2016-10-01

    In India, Vatari Guggulu has been traditionally used in the Ayurvedic system of medicine to treat rheumatoid arthritis (RA). The current study was undertaken to evaluate anti-arthritic activity of alcoholic extract of Vatari Guggulu in rats. Arthritis was induced by administration of formaldehyde (2%v/v) or Complete Freund's Adjuvant (CFA) into the sub-plantar surface of left hind paw of the animals. The extract was administered to the rats by oral gavages in different doses. Joint swelling was measured in formaldehyde induced arthritis. Various physical, biochemical and histopathological parameters were determined in CFA induced arthritis. Vatari Guggulu extract (VGE) produced significant (P < 0.05) inhibition of joint swelling in both formaldehyde and CFA induced arthritis. The treatment also brought to normalcy the increased white blood cell (WBC) count, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), cholesterol, triglycerides and LDL with an enhancement of haemoglobin (Hb) levels and red blood cell (RBC) count. These effects were found to be dose dependent. These effects were comparable with standard drug indomethacin. Histo-pathological studies of the ankles of VGE treated animals exhibited significant improvements. VGE did not show any toxic symptoms even at a dose of 2000 mg/kg in acute toxicity studies on rats. Thus, Vatari Guggulu, a classical Ayurvedic formulation of the Indian System of Medicine, exhibited significant anti-arthritic activity in formaldehyde and CFA induced arthritis in rats. This study corroborates the claims of Ayurveda on Vatari Guggulu.

  15. 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

  16. 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.

  17. Assessment of anti-inflammatory and anti-arthritic properties of Acmella uliginosa (Sw.) Cass. based on experiments in arthritic rat models and qualitative gas chromatography-mass spectrometry analyses

    PubMed Central

    Paul, Subhashis; Sarkar, Sudeb; Dutta, Tanmoy; Bhattacharjee, Soumen

    2016-01-01

    Aim: The principle objective of the study was to explore the anti-arthritic properties of Acmella uliginosa (AU) (Sw.) Cass. flower in a rat model and to identify potential anti-inflammatory compounds derived from flower extracts. The synergistic role played by a combination of AU flower and Aloe vera (AV) gel crude extracts was also investigated. Materials and Methods: Male Wistar rats induced with Freund’s complete adjuvant (FCA) were used as a disease model of arthritic paw swelling. There were three experimental and two control groups, each consisting of five rats. Paw circumference and serum biochemical parameters were evaluated to investigate the role of the flower extracts in disease amelioration through a feeding schedule spanning 21 days. Gas chromatography/mass spectrometry (GC/MS) analyses were performed to search for the presence of anti-inflammatory compounds in the ethanolic and n-hexane solvent extracts of the flower. Results: As a visual cue to the experimental outcomes, FCA-induced paw swelling decreased to the normal level; and hemoglobin, serum protein, and albumin levels were significantly increased in the treated animals. The creatinine level was estimated to be normal in the experimental rats after the treatment. The combination of AU and AV showed the best recovery potential in all the studied parameters, confirming the synergistic efficacy of the herbal formulation. GC/MS analyses revealed the presence of at least 5 anti-inflammatory compounds including 9-octadecenoic acid (Z)-, phenylmethyl ester, astaxanthin, à-N-Normethadol, fenretinide that have reported anti-inflammatory/anti-arthritic properties. Conclusion: Our findings indicated that the crude flower homogenate of AU contains potential anti-inflammatory compounds which could be used as an anti-inflammatory/anti-arthritic medication. PMID:27366352

  18. 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.

  19. Effect of ethanol extract of Trigonella foenum graecum (Fenugreek) seeds on Freund's adjuvant-induced arthritis in albino rats.

    PubMed

    Suresh, P; Kavitha, Ch N; Babu, S Manohar; Reddy, V Prabhakar; Latha, A Kanaka

    2012-08-01

    Trigonella foenum graecum is an Iranian medicinal plant used for the treatment of rheumatoid arthritis and inflammation. The present study was designed to investigate the beneficial outcome of the plant T. foenum graecum on adjuvant-induced arthritis in albino rats. Ethanol extract of T. foenum graecum was tested against Freund's complete adjuvant-induced arthritis in rats. In the present study, paw volume was measured on the 4th, 8th, 14th and 21st day. On day 22, animals were anaesthetized, and blood samples were collected for the estimation of haemoglobin, white blood cells (WBC), differential white blood cells, erythrocyte sedimentation rate (ESR), red blood cells (RBC), interleukins (IL-1α, IL-1β, IL-2, IL-6) and tumour necrosis factor-α (TNF-α). The animals were sacrificed, and the cartilage tissue was isolated for estimation of lipid peroxidation (LPO), superoxide dismutase (SOD) and glutathione (GSH). Administration with both doses of T. foenum graecum (200 and 400 mg/kg) significantly (P < 0.05) decreased the paw oedema and restored body weight. T. foenum graecum significantly (P < 0.05) reduced the differential WBC count, ESR and WBC (5.833 ± 0.703, 6.989 ± 58.5) content and also showed significant (P < 0.05) increase in RBC and Hb (4.783 ± 0.46, 15.46 ± 0.158) content. T. foenum graecum significantly (P < 0.05) decreased the IL-1α, IL-1β, IL-2, IL-6 and TNF-α levels. It also significantly decreased the levels of LPO and increased the SOD and GSH levels in cartilage tissue. In this study, T. foenum graecum 400-mg/kg dose showed more prominent results compared to the 200-mg/kg dose of T. foenum graecum. The results obtained in this study suggest that anti-inflammatory and antioxidant activities of T. foenum graecum may be the possible reason behind the observed anti-arthritic activity.

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. Multi-response model for rheumatoid arthritis based on delay differential equations in collagen-induced arthritic mice treated with an anti-GM-CSF antibody.

    PubMed

    Koch, Gilbert; Wagner, Thomas; Plater-Zyberk, Christine; Lahu, Gezim; Schropp, Johannes

    2012-02-01

    Collagen-induced arthritis (CIA) in mice is an experimental model for rheumatoid arthritis, a human chronic inflammatory destructive disease. The therapeutic effect of neutralizing the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) by an antibody was examined in the mouse disease in a view of deriving a pharmacokinetic/pharmacodynamic (PKPD) model. In CIA mice the development of disease is measured by a total arthritic score (TAS) and an ankylosis score (AKS). We present a multi-response PKPD model which describes the time course of the unperturbed and perturbed TAS and AKS. The antibody acts directly on GM-CSF by binding to it. Therefore, a compartment for the cytokine GM-CSF is an essential component of the mathematical model. This compartment drives the disease development in the PKPD model. Different known properties of arthritis development in the CIA model are included in the PKPD model. Firstly, the inflammation, driven by GM-CSF, dominates at the beginning of the disease and decreases after some time. Secondly, a destructive (ankylosis) part evolves in the TAS that is delayed in time. In order to model these two properties a delay differential equation was used. The PKPD model was applied to different experiments with doses ranging from 0.1 to 100 mg/kg. The influence of the drug was modeled by a non-linear approach. The final mathematical model consists of three differential equations representing the compartments for GM-CSF, inflammation and destruction. Our mathematical model described well all available dosing schedules by a simultaneous fit. We also present an equivalent and easy reformulation as ordinary differential equation which grants the use of standard PKPD software.

  5. 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.

  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. Aqueous fraction of Alstonia boonei de Wild leaves suppressed inflammatory responses in carrageenan and formaldehyde induced arthritic rats.

    PubMed

    Akinnawo, Omowumi O; Anyasor, God'swill N; Osilesi, Odutola

    2017-02-01

    Alstonia boonie de Wild is an ethnomedical plant used as therapy against inflammatory disorders. This study evaluated the most active anti-inflammatory and anti-oxidant fraction of A. boonei leaves using in vitro and in vivo models. Quantitative phytochemical analysis, anti-protein denaturation and hypotonicity-induced hemolysis of human red blood cell membrane (HRBC), radical scavenging activity assays, carrageenan and formaldehyde-induced inflammation models were carried out. Results showed that aqueous and ethyl acetate fractions of 70% methanol extract of A. boonie leaves contained high quantities of total phenolic and flavonoid compounds compared with hexane and butanol fractions. Aqueous fraction of A. boonie leaves significantly (P<0.05) inhibited heat-induced protein denaturation, stabilized hypotonicity-induced hemolysis of HRBC, scavenged DPPH, NO and H2O2 radicals in a concentration-dependent manner compared with other fractions in vitro. In addition, orally administered 50-250-mg/kg body weight (b.w.) aqueous fraction of A. boonei leaves suppressed carrageenan-induced rat paw edema thickness by 74.32%, 79.22% and 89.86% respectively at 6th h in a dose-dependent manner comparable with animals treated with standard diclofenac sodium (88.69%) in vivo. Furthermore, investigation of formaldehyde-induced inflammation in rats showed that 50-250 mg/kg b.w. aqueous fraction of A. boonei reduced plasma alanine aminotransferase and aspartate aminotransferase activities. Aqueous fraction of A. boonei also suppressed eosinophils, monocytes and basophils, total white blood cell, total platelet, neutrophil and lymphocyte counts and modulated plasma lipid profile compared with control group. Aqueous fraction of A. boonei leaves exhibited substantial active anti-inflammatory and antioxidant activities. Hence, an aqueous fraction of A. boonei leaves could be channeled towards pharmaceutical drug development. In addition, this study provided scientific insight to account

  8. The Preventive Effects of Nanopowdered Peanut Sprout-added Caciocavallo Cheese on Collagen-induced Arthritic Mice.

    PubMed

    Kim, Dong-Hwi; Chang, Yoon Hyuk; Kwak, Hae-Soo

    2014-01-01

    The present study was carried out to investigate the effects of nanopowdered peanut sprout-added Caciocavallo cheese (NPCC) on the prevention and treatment of rheumatoid arthritis in DBA/IJ mice immunized with type II collagen. After the induction of arthritis, the mice were being divided into five groups: (1) normal, no immunization; (2) CIA, collagen-induced arthritis; (3) MTX, collagen-induced arthritis treated with methotrexate (0.3 mg/kg body weight); (4) CC, collagen-induced arthritis treated with Caciocavallo cheese (0.6 g/d); (5) NPCC, collagen-induced arthritis treated with nanopowdered peanut sprout-added Caciocavallo cheese (0.6 g/d). Nanopowdered peanut sprout was ranged from 300 to 350 nm, while regular powdered peanut sprouts were ranged from 50 to 150 μm. The NPCC group had considerable reductions of clinical scores and paw thicknesses at the end of experiment as compared to the CIA group. In the serum analysis, the TNF-α, IL-1β, IL- 6 and IgG1 levels in the NPCC group have decreased by 69.4, 75.9, 66.6, and 61.9%, respectively, when compared to the CIA group. The histological score and spleen index of the NPCC group were significantly lower than the CIA group. In conclusion, the feeding NPCC method could delay and/or prevent the rheumatoid arthritis in the collagen-induced arthritis mouse model. Based on this study, nanopowdered peanut sprouts could be applied to various functional cheeses.

  9. The Preventive Effects of Nanopowdered Peanut Sprout-added Caciocavallo Cheese on Collagen-induced Arthritic Mice

    PubMed Central

    Chang, Yoon Hyuk

    2014-01-01

    The present study was carried out to investigate the effects of nanopowdered peanut sprout-added Caciocavallo cheese (NPCC) on the prevention and treatment of rheumatoid arthritis in DBA/IJ mice immunized with type II collagen. After the induction of arthritis, the mice were being divided into five groups: (1) normal, no immunization; (2) CIA, collagen-induced arthritis; (3) MTX, collagen-induced arthritis treated with methotrexate (0.3 mg/kg body weight); (4) CC, collagen-induced arthritis treated with Caciocavallo cheese (0.6 g/d); (5) NPCC, collagen-induced arthritis treated with nanopowdered peanut sprout-added Caciocavallo cheese (0.6 g/d). Nanopowdered peanut sprout was ranged from 300 to 350 nm, while regular powdered peanut sprouts were ranged from 50 to 150 μm. The NPCC group had considerable reductions of clinical scores and paw thicknesses at the end of experiment as compared to the CIA group. In the serum analysis, the TNF-α, IL-1β, IL- 6 and IgG1 levels in the NPCC group have decreased by 69.4, 75.9, 66.6, and 61.9%, respectively, when compared to the CIA group. The histological score and spleen index of the NPCC group were significantly lower than the CIA group. In conclusion, the feeding NPCC method could delay and/or prevent the rheumatoid arthritis in the collagen-induced arthritis mouse model. Based on this study, nanopowdered peanut sprouts could be applied to various functional cheeses. PMID:26760745

  10. The Protective Effect of Yi Shen Juan Bi Pill in Arthritic Rats with Castration-Induced Kidney Deficiency

    PubMed Central

    Zhao, Hongyan; Li, Jian; He, Xiaojuan; Lu, Cheng; Xiao, Cheng; Niu, Xuyan; Zhao, Ning; Ju, Dahong; Lu, Aiping

    2012-01-01

    Androgens have been linked to the onset, severity, and progression of rheumatoid arthritis (RA). In traditional Chinese medicine (TCM), the most common pattern in RA is kidney deficiency, which partly corresponds to a low sex hormone state. In this study, TCM kidney deficiency was induced in male Sprague-Dawley rats with castration surgery, and a TCM preparation, Yi Shen Juan Bi Pill (YJB), was used to treat collagen induced arthritis (CIA) rats with castration. Metabolomic technique was used to evaluate the pharmacological mechanism in castrated CIA rats treated by YJB. The results showed that castration significantly increased the severity of the arthritis in rats but was ameliorated by YJB. Its pharmacological mechanism was partially associated with lipid metabolites involving free fatty acid (FFA) and lysophosphatidylcholine (LPC). In conclusion, the experimental results demonstrate the protective effect of YJB on the TCM kidney deficiency pattern induced by androgen deficiency in CIA rats and support that YJB should be used for the clinical treatment of RA with TCM kidney deficiency pattern. PMID:22550538

  11. Designation of a novel DKK1 multiepitope DNA vaccine and inhibition of bone loss in collagen-induced arthritic mice.

    PubMed

    Zhang, Xiaoqing; Liu, Sibo; Li, Shentao; Du, Yuxuan; Dou, Yunpeng; Li, Zhanguo; Yuan, Huihui; Zhao, Wenming

    2015-01-01

    Dickkopf-1 (DKK1), a secretory inhibitor of canonical Wnt signaling, plays a critical role in certain bone loss diseases. Studies have shown that serum levels of DKK1 are significantly higher in rheumatoid arthritis (RA) patients and are correlated with the severity of the disease, which indicates the possibility that bone erosion in RA may be inhibited by neutralizing the biological activity of DKK1. In this study, we selected a panel of twelve peptides using the software DNASTAR 7.1 and screened high affinity and immunogenicity epitopes in vitro and in vivo assays. Furthermore, we optimized four B cell epitopes to design a novel DKK1 multiepitope DNA vaccine and evaluated its bone protective effects in collagen-induced arthritis (CIA), a mouse model of RA. High level expression of the designed vaccine was measured in supernatant of COS7 cells. In addition, intramuscular immunization of BALB/c mice with this vaccine was also highly expressed and sufficient to induce the production of long-term IgG, which neutralized natural DKK1 in vivo. Importantly, this vaccine significantly attenuated bone erosion in CIA mice compared with positive control mice. These results provide evidence for the development of a DNA vaccine targeted against DKK1 to attenuate bone erosion.

  12. Designation of a Novel DKK1 Multiepitope DNA Vaccine and Inhibition of Bone Loss in Collagen-Induced Arthritic Mice

    PubMed Central

    Zhang, Xiaoqing; Liu, Sibo; Li, Shentao; Du, Yuxuan; Dou, Yunpeng; Li, Zhanguo; Yuan, Huihui; Zhao, Wenming

    2015-01-01

    Dickkopf-1 (DKK1), a secretory inhibitor of canonical Wnt signaling, plays a critical role in certain bone loss diseases. Studies have shown that serum levels of DKK1 are significantly higher in rheumatoid arthritis (RA) patients and are correlated with the severity of the disease, which indicates the possibility that bone erosion in RA may be inhibited by neutralizing the biological activity of DKK1. In this study, we selected a panel of twelve peptides using the software DNASTAR 7.1 and screened high affinity and immunogenicity epitopes in vitro and in vivo assays. Furthermore, we optimized four B cell epitopes to design a novel DKK1 multiepitope DNA vaccine and evaluated its bone protective effects in collagen-induced arthritis (CIA), a mouse model of RA. High level expression of the designed vaccine was measured in supernatant of COS7 cells. In addition, intramuscular immunization of BALB/c mice with this vaccine was also highly expressed and sufficient to induce the production of long-term IgG, which neutralized natural DKK1 in vivo. Importantly, this vaccine significantly attenuated bone erosion in CIA mice compared with positive control mice. These results provide evidence for the development of a DNA vaccine targeted against DKK1 to attenuate bone erosion. PMID:26075259

  13. Lactobacillus casei and Lactobacillus acidophilus regulate inflammatory pathway and improve antioxidant status in collagen-induced arthritic rats.

    PubMed

    Amdekar, Sarika; Singh, Vinod; Kumar, Avnish; Sharma, Poonam; Singh, Rambir

    2013-01-01

    In view of well-established immunomodulatory properties of Lactobacillus, present investigation was carried out to evaluate antioxidant and anti-inflammatory potential of Lactobacillus casei and Lactobacillus acidophilus, against inflammatory pathway and oxidative stress developed in an experimental model of arthritis. Collagen-induced arthritis (CIA) model was used. Oral administration of L. casei, L. acidophilus, standard antiarthritic drug indomethacin, and vehicle were started after induced arthritis and continued up to day 28. Interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, IL-17, IL-4, and IL-10 levels were estimated in serum. In parallel, oxidative stress parameters were also measured from synovial effsuate. All rats were graded for arthritis score at the end of each week. L. casei, L. acidophilus, and indomethacin treatment significantly downregulated proinflammatory and upregulated anti-inflammatory cytokines at P<0.0001. They have significantly decreased oxidative stress in synovial effsuate (P<0.0001) and also arthritis score (P<0.05). Protection provided by L. casei and L. acidophilus was more pronounced than that of indomethacin. These lines of evidence suggest that L. casei and L. acidophilus exert potent protective effect against CIA. It further establishes effective anti-inflammatory and antioxidant properties of Lactobacillus. However, additional clinical investigations are needed to prove the efficacy of Lactobacillus in treatment/management of rheumatoid arthritis.

  14. 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.

  15. Preliminary evaluation of anti-inflammatory and anti-arthritic activity of S. lappa, A. speciosa and A. aspera.

    PubMed

    Gokhale, A B; Damre, A S; Kulkami, K R; Saraf, M N

    2002-07-01

    Saussurea lappa, Argyreia speciosa and Achyranthes aspera are well known Indian medicinal plants used in the indigenous systems of medicine for the treatment of inflammatory conditions. The ethanolic extracts of the plants at the doses of 50, 100 and 200 mg/kg, p.o. were screened for their effect on acute and chronic inflammation induced in mice and rats. S. lappa and A. speciosa were found to significantly inhibit paw edema induced by carrageenan and Freund's complete adjuvant and to prevent accumulation of inflammatory cells in carrageenan-induced peritonitis at doses of 50-200 mg/kg. A. aspera inhibited these inflammatory responses at doses of 100-200 mg/kg. The studies reveal that the ethanolic extracts of S. lappa, A. speciosa and A. aspera possess anti-inflammatory and anti-arthritic activity and support the rationale behind the traditional use of these plants in inflammatory conditions.

  16. Modeling Pharmacokinetics/Pharmacodynamics of Abatacept and Disease Progression in Collagen-Induced Arthritic Rats - A Population Approach

    PubMed Central

    Lon, Hoi-Kei; Liu, Dongyang; DuBois, Debra C.; Almon, Richard R.

    2013-01-01

    The PK / PD of abatacept, a selective T-cell co-stimulation modulator, was examined in rats with collagen-induced arthritis (CIA) using a nonlinear mixed effect modeling approach. Male Lewis rats underwent collagen induction to produce rheumatoid arthritis. Two single-dose groups received either 10 mg/kg intravenous (IV) or 20 mg/kg subcutaneous (SC) abatacept, and one multiple-dose group received one 20 mg/kg SC abatacept dose and four additional 10 mg/kg SC doses. Effects on disease progression (DIS) were measured by paw swelling. Plasma concentrations of abatacept were assayed by enzyme-linked immunosorbent assay (ELISA). The PK / PD data were sequentially fitted using NONMEM VI. Goodness-of-fit was assessed by objective functions and visual inspection of diagnostic plots. The PK of abatacept followed a two-compartment model with linear elimination. For SC doses, short-term zero-order absorption was assumed with F = 59.2 %. The disease progression component was an indirect response model with a time-dependent change in paw edema production rate constant (kin) that was inhibited by abatacept. Variation in the PK data could be explained by inter-individual variability in clearance (CL) and central compartment volume (V1), while the large variability of the PD data may be the result of paw edema production (kin0) and loss rate constant (kout). Abatacept has modest effects on paw swelling in CIA rats. The PK / PD profiles were well described by the proposed model and allowed evaluation of inter-individual variability on drug- and DIS-related parameters. PMID:24233383

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

    PubMed

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

    2011-08-01

    Turmeric (rich in curcuminoids) and ginger (rich in gingerols and shogaols) rhizomes have been widely used as dietary spices and to treat different diseases in Ayurveda/Chinese medicine since antiquity. Here, we compared the anti-inflammatory/anti-oxidant activity of these two plants in rat adjuvant-induced arthritis (AIA). Both plants (at dose 200 mg/kg body weight) significantly suppressed (but with different degrees) the incidence and severity of arthritis by increasing/decreasing the production of anti-inflammatory/pro-inflammatory cytokines, respectively, and activating the anti-oxidant defence system. The anti-arthritic activity of turmeric exceeded that of ginger and indomethacin (a non-steroidal anti-inflammatory drug), especially when the treatment started from the day of arthritis induction. The percentage of disease recovery was 4.6-8.3% and 10.2% more in turmeric compared with ginger and indomethacin (P < 0.05), respectively. The present study proves the anti-inflammatory/anti-oxidant activity of turmeric over ginger and indomethacin, which may have beneficial effects against rheumatoid arthritis onset/progression as shown in AIA rat model.

  18. 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.

  19. Oral curcumin has anti-arthritic efficacy through somatostatin generation via cAMP/PKA and Ca(2+)/CaMKII signaling pathways in the small intestine.

    PubMed

    Yang, Yan; Wu, Xin; Wei, Zhifeng; Dou, Yannong; Zhao, Di; Wang, Ting; Bian, Difei; Tong, Bei; Xia, Ying; Xia, Yufeng; Dai, Yue

    2015-01-01

    Curcumin (CUR) has been proven to be clinically effective in rheumatoid arthritis (RA) therapy, but its low oral bioavailability eclipses existent evidence that attempts to explain the underlying mechanism. Small intestine, the only organ exposed to a relatively high concentration of CUR, is the main site that generates gut hormones which are involved in the pathogenesis of RA. This study aims at addressing the hypothesis that one or more gut hormones serve as an intermediary agent for the anti-arthritic action of CUR. The protein and mRNA levels of gut hormones in CUR-treated rats were analyzed by ELISA and RT-PCR. Somatostatin (SOM) depletor and receptor antagonist were used to verify the key role of SOM in CUR-mediated anti-arthritic effect. The mechanisms underlying CUR-induced upregulation of SOM levels were explored by cellular experiments and immunohistochemical staining. The data showed that oral administration of CUR (100 mg/kg) for consecutive two weeks in adjuvant-induced arthritis rats still exhibited an extremely low plasma exposure despite of a dramatic amelioration of arthritis symptoms. When injected intraperitoneally, CUR lost anti-arthritic effect in rats, suggesting that it functions in an intestine-dependent manner. CUR elevated SOM levels in intestines and sera, and SOM depletor and non-selective SOM receptor antagonist could abolish the inhibitory effect of CUR on arthritis. Immunohistochemical assay demonstrated that CUR markedly increased the number of SOM-positive cells in both duodenum and jejunum. In vitro experiments demonstrated that CUR could augment SOM secretion from intestinal endocrine cells, and this effect could be hampered by either MEK1/2 or Ca(2+)/calmodulin-dependent kinase II (CAMKII) inhibitor. In summary, oral administration of CUR exhibits anti-arthritic effect through augmenting SOM secretion from the endocrine cells in small intestines via cAMP/PKA and Ca(2+)/CaMKII signaling pathways.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. 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

  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. Effect of genetic deletion of the vanilloid receptor TRPV1 on the expression of Substance P in sensory neurons of mice with adjuvant-induced arthritis

    PubMed Central

    Willcockson, Helen H.; Chen, Yong; Han, Ji Eun; Valtschanoff, Juli G.

    2010-01-01

    The neuropeptide Substance P (SP), expressed by nociceptive sensory afferents in joints, plays an important role in the pathogenesis of arthritis. Capsaicin causes neurons in the dorsal root ganglia (DRG) to release SP from their central and peripheral axons, suggesting a functional link between SP and the capsaicin receptor, the transient receptor potential vanilloid 1 (TRPV1). The expression of both TRPV1 and SP have been reported to increase in several models of arthritis but the specific involvement of TRPV1-expressing articular afferents that can release SP is not completely understood. We here wanted to ascertain whether the increase in the number of SP-positive primary afferents in arthritis may be affected by genetic deletion of TRPV1. For this, we used immunohistochemistry to quantify the expression of SP in primary afferent neurons in wild type mice (WT) vs. TRPV1-knockout (KO) mice with adjuvant-induced arthritis (AIA). We found that the expression of SP in DRG 1) increased significantly over naïve level in both WT and KO mice 3 weeks after AIA, 2) was significantly higher in KO mice than in WT mice in naïve mice and 2-3 weeks after AIA, 3) was significantly higheron the side of AIA than on the contralateral, vehicle-injected side at all time points in WT mice, but not in KO mice, and 4) increased predominantly in small-size neurons in KO mice and in small- and medium-size neurons in WT mice. Since the size distribution of SP-positive DRG neurons in arthritic TRPV1-KO mice was not significantly different from that in naïve mice, we speculate that the increased expression of SP is unlikely to reflect recruitment of A-fiber primary afferents and that the higher expression of SP in KO mice may represent a plastic change to compensate for the missing receptor in a major sensory circuit. PMID:20303589

  9. 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

  10. Treatment with anti-NAP monoclonal antibody reduces disease severity in murine model of novel angiogenic protein-induced or ovalbumin-induced arthritis.

    PubMed

    Nataraj, N B; Krishnamurthy, J; Salimath, B P

    2013-02-01

    Rheumatoid arthritis (RA) is a polyarticular inflammatory, angiogenic disease. Synovial angiogenesis contributes to inflammation in RA. In this study we have developed an arthritic model in rats using a novel angiogenic protein (NAP), isolated from human synovial fluid of RA patients. We produced anti-NAP monoclonal antibodies (mAbs) and investigated the therapeutic efficacy of the same in adjuvant-induced or NAP-induced arthritis as a model of human RA. The treatment of arthritic rats with anti-NAP mAbs resulted in effective amelioration of paw oedema, radiological arthritic characteristics, serum levels of vascular endothelial growth factor (VEGF) and NAP, compared to that of untreated arthritic animals. Further, profiling of angiogenic markers such as synovial microvessel density, angiogenesis, CD31, VEGF and fms-like tyrosine kinase (Flt1) by immunohistochemistry both in arthritic and anti-NAP mAb-treated animals revealed the efficacy of mAb as an anti-angiogenic functional antibody. Therefore, NAP may be an attractive target to design anti-angiogenic and anti-arthritic therapies to control the pathogenesis of arthritis.

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. Immunity to heat shock proteins and arthritic disorders.

    PubMed Central

    van Eden, W

    1999-01-01

    Adjuvant arthritis (AA) is a frequently used model of experimental arthritis. Because of its histopathology, which is reminiscent of rheumatoid arthritis in humans, AA is used as a model for the development of novel anti-inflammatory drugs. Recently, it has become evident that AA is a typical T-cell-mediated autoimmune condition. Therefore, novel immunotherapies targeted to T cells can be developed in this model. Analysis of responding T cells in AA have now led to the definition of various antigens with potential relevance to arthritis, including human arthritic conditions. One such antigen defined in AA is the 60kD heat shock protein. Both T-cell vaccination approaches and active antigen immunizations and antigen toleration approaches have turned out to be effective in suppressing AA. PMID:10231009

  16. Trikatu, an herbal compound ameliorates rheumatoid arthritis by the suppression of inflammatory immune responses in rats with adjuvant-induced arthritis and on cultured fibroblast like synoviocytes via the inhibition of the NFκB signaling pathway.

    PubMed

    Doss, Hari Madhuri; Ganesan, Ramamoorthi; Rasool, Mahaboobkhan

    2016-10-25

    The present study was designed to investigate the potential therapeutic effect of trikatu, an herbal compound and its underlying molecular mechanism in rats with adjuvant-induced arthritis (AIA). Our results indicate that trikatu (1000 mg/kg/b.wt. oral) administration suppressed the production of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein (MCP)-1) and downregulated the mRNA expression levels of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-17, MCP-1, receptor activator of nuclear factor kappa B ligand (RANKL), cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS)) and transcription factors (nuclear factor kappa B 65 (NFкB-p65) and activator protein-1 (AP-1)) in cultured AIA-fibroblast like synoviocytes and synovial tissue of AIA rats. Consistently, the protein expression of NFкB-p65, IL-17, TNF-α, COX-2, and RANKL was also dramatically reduced in cultured AIA-fibroblast like synoviocytes and synovial tissue of AIA rats by trikatu treatment. In addition, trikatu suppressed the expression and phosphorylation of NFкB-p65 similar to the Bay 11-7082 (NFкB inhibitor) in cultured AIA-fibroblast like synoviocytes. Furthermore, trikatu alleviated the histopathology of joint of arthritic rats. Overall, these data highlights that trikatu could be a promising alternative modality for the possible treatment of rheumatoid arthritis and other inflammatory diseases.

  17. The melanocortin receptor type 3 agonist d‐Trp(8)‐γMSH decreases inflammation and muscle wasting in arthritic rats

    PubMed Central

    Gómez‐SanMiguel, Ana Belen; Martín, Ana Isabel; Nieto‐Bona, María Paz; Fernández‐Galaz, Carmen; Villanúa, María Ángeles

    2015-01-01

    Abstract Background Chronic inflammatory diseases induce cachexia that increases mortality and morbidity of the illness. Adjuvant‐induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. Alpha‐melanocyte stimulating hormone has an anti‐inflammatory effect in arthritic rats and decreases muscle wasting. The aim of this work was to elucidate whether the anti‐cachectic action of alpha‐melanocyte stimulating hormone is mediated by the melanocortin receptor type 3 pathway. Methods Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant, and 6 days afterwards, arthritic rats were injected with the selective melanocortin receptor type 3 agonist d‐Trp(8)‐gammaMSH ( d‐Trp(8)‐γMSH) 500 µg/kg subcutaneously. or saline twice a day, for 10 days. Results d‐Trp(8)‐γMSH decreased the external signs of inflammation and body weight loss, but it was not able to modify the anorexigenic effect of arthritis or the increase in hypothalamic cyclooxygenase‐2 (COX‐2) expression. In contrast, d‐Trp(8)‐γMSH prevented arthritis‐induced increase in hypothalamic IL‐1β and serum corticosterone levels and the decrease in serum IGF‐I levels. d‐Trp(8)‐γMSH treatment also prevented arthritis‐induced NF‐kB(p65) phosphorylation and tumour necrosis factor‐α mRNA increase in the gastrocnemius. d‐Trp(8)‐γMSH administration to arthritic rats increased gastrocnemius mass, its cross‐sectional area, and mean fast fibre area. Those effects of d‐Trp(8)‐γMSH were associated with a decreased expression of atrogin‐1 and muscle ring‐finger protein‐1 in the gastrocnemius. In rats treated with saline, arthritis increased the expression of autophagy marker genes LC3b, Bnip‐3, and Gabarap1 as well as the conversion of LC3b I to LC3b II by lipidation in the gastrocnemius. d‐Trp(8)‐γMSH decreased gastrocnemius LC3b, Bnip‐3, and Gabarap

  18. Effect of methotrexate on the mandibular development of arthritic rabbits

    PubMed Central

    Meyer, Philipp; Rafayelyan, Smbat; Minden, Kirsten; Jost-Brinkmann, Paul-Georg

    2015-01-01

    Summary Introduction: Juvenile idiopathic arthritis affecting the temporomandibular joint (TMJ) can cause severe disturbances of the mandibular development. Methotrexate (MTX) is often administered as a common used remission-inducing agent to treat this disease. The aim of this study was to investigate the effect of low dose MTX on the mandibular growth in arthritic rabbits. Subjects and methods: Eighteen 10-week-old female New Zealand white rabbits were randomly assigned to three groups with six animals in each group. After being sensitized to ovalbumin (OA), the first and the second group received intra-articular injections with OA. The first group remained untreated, the second was treated by weekly injections of MTX. Cephalograms were taken from each animal at 10, 13, 16, 19, and 22 weeks of age and six mandibular distances measured. Results: All distances showed an increase between 10 and 20 per cent, whereas growth was more accentuated in the sagittal dimension. Significant differences in the overall growth could be observed between the arthritic and the control animals and less accentuated between the arthritic and the MTX animals. In contrast, existing differences between the groups were not significant during the intervals, but time had the greatest influence on mandibular growth. Conclusions: MTX seems to have a positive impact on growth in rabbits suffering from experimental arthritis of the TMJ. PMID:25518996

  19. 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.

  20. Periodontitis increases rheumatic factor serum levels and citrullinated proteins in gingival tissues and alter cytokine balance in arthritic rats

    PubMed Central

    Corrêa, Mônica G.; Sacchetti, Silvana B.; Ribeiro, Fernanda Vieira; Pimentel, Suzana Peres; Casarin, Renato Corrêa Viana; Cirano, Fabiano Ribeiro; Casati, Marcio Z.

    2017-01-01

    This study investigated some immunological features by experimental periodontitis (EP) and rheumatoid arthritis (RA) disease interact in destructive processes in arthritic rats. Rats were assigned to the following groups: EP +RA; RA; EP; and Negative Control. RA was induced by immunizations with type-II collagen and a local immunization with Complete Freund’s adjuvant in the paw. Periodontitis was induced by ligating the right first molars. The serum level of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACCPA) were measured before the induction of EP (T1) and at 28 days after (T2) by ELISA assay. ACCPA levels were also measured in the gingival tissue at T2. The specimens were processed for morphometric analysis of bone loss, and the gingival tissue surrounding the first molar was collected for the quantification of interleukin IL-1β, IL-4, IL-6, IL-17 and TNF-α using a Luminex/MAGpix assay. Paw edema was analyzed using a plethysmometer. Periodontitis increased the RF and ACCPA levels in the serum and in the gingival tissue, respectively. Besides, the level of paw swelling was increased by EP and remained in progress until the end of the experiment, when EP was associated with RA. Greater values of IL-17 were observed only when RA was present, in spite of PE. It can be concluded that periodontitis increases rheumatic factor serum levels and citrullinated proteins level in gingival tissues and alter cytokine balance in arthritic rats; at the same time, arthritis increases periodontal destruction, confirming the bidirectional interaction between diseases. PMID:28358812

  1. Inhibitory properties of triethylphosphine goldlupinylsulfide in adjuvant-induced arthritis in rats.

    PubMed

    Ghia, M; Mattioli, F; Novelli, F; Minganti, V

    1995-09-01

    A new gold coordination compound (triethylphosphine goldlupinylsulfide: TP-Au-LS) was tested in adjuvant-induced arthritis in the rat, by oral administration at doses of 5, 10 and 20 mg/kg/day of gold for 17 consecutive days, in comparison with auranofin and betamethasone. TP-Au-LS produced a dose dependent reduction of both the injected and uninjected hind paw volume. Gold levels in serum (measured on day 18 by inductively coupled plasma atomic emission spectrometry) were also found to be dose related. At the dose of 10 mg/kg, TP-Au-LS and auranofin induced superimposable reductions of the injected paw volume; however the first drug produced higher serum gold concentrations than those achieved with the latter.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. The effects of 5-HT on articular sensory receptors in normal and arthritic rats.

    PubMed Central

    Birrell, G. J.; McQueen, D. S.; Iggo, A.; Grubb, B. D.

    1990-01-01

    1. The effects of intra arterial (i.a.) injections of 5-hydroxytryptamine (5-HT, 1-100 micrograms) on the discharge of (a) identified articular high threshold mechanoreceptors and (b) unidentified chemosensitive receptors in the ankle joint have been studied electrophysiologically in anaesthetized normal and arthritic rats. Recordings were made from a fine branch of the medial plantar nerve. 2. 5-HT increased the mechanical responsiveness of high threshold nociceptive mechanoreceptors with C and A delta fibre afferents in both normal and adjuvant-arthritic rats. Receptors in arthritic joints were more sensitive to 5-HT than were those from normal joints. 3. 5-HT produced a complex response from both types of articular receptors following i.a. injection. Two separate components were identified: (a) a fast transient burst of activity was obtained within 10 s of this injection in 66% of units from normal animals and 45% from arthritics, followed by (b) a delayed slow longer-lasting excitation seen in 62% of the units examined from normals and 77% of units from arthritic rats. 4. Increased mechanoreceptor responsiveness produced by 5-HT was reduced or abolished by the 5-HT3 receptor antagonists studied (MDL 72222, ICS 205-930, or GR 38032F, in single doses of 100 micrograms kg-1, i.a.). 5. Fast excitation showed marked tachyphylaxis and was antagonized by MDL 72222, ICS 205-930 or GR 38032F. It was unaffected by ketanserin (100 micrograms kg-1, i.a.). Delayed excitation was reduced or abolished by ketanserin but was unaffected by the 5-HT3-receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2076487

  7. Adjuvant arthritis pretreatment with type II collagen and Mycobacterium butyricum.

    PubMed

    Franch, A; Cassany, S; Castellote, C; Castell, M

    1992-11-01

    A treatment previous to adjuvant arthritis induction has been performed with type II collagen (CII) or Mycobacterium butyricum (Mb), which is the inducer of the pathology. Pretreatment was administered in two different ways: a) subcutaneously or intradermally 14 days before arthritis induction, and b) intravenously 3 days before induction. In order to relate the change in inflammation to the corresponding antigen immune response, serum antibodies and delayed type hypersensitivity (DTH) against CII or Mb were studied. Pretreatment with s.c. CII 14 days before induction produced slight protection against arthritis and significantly delayed its onset; systemic inflammation showed good positive correlation with anti-CII antibodies. The CII administered i.v. 3 days before arthritic challenge did not significantly modify the inflammatory process. The use of i.d. subarthritogenic doses of Mb 14 days before induction protected a high percentage of the animals from the posterior arthritic challenge; this protection was accompanied by high anti-Mb antibody titers and DTH reaction. When Mb was given i.v. 3 days before induction, a partial protection of inflammation was observed; arthritis was milder and its onset was delayed. These changes were accompanied by reduced humoral and cellular response to Mb.

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. Aerobic Exercise Prescription for Rheumatoid Arthritics.

    ERIC Educational Resources Information Center

    Evans, Blanche W.; Williams, Hilda L.

    The use of exercise as a general treatment for rheumatoid arthritics (RA) has included range of motion, muscular strength, water exercise and rest therapy while virtually ignoring possible benefits of aerobic exercise. The purposes of this project were to examine the guidelines for exercise prescription in relation to this special population and…

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. In vivo and in vitro effects of dexamethasone on leukocyte migration in the rat adjuvant arthritis model

    SciTech Connect

    Thieme, T.R.; Mirkovich, A.; Maloney, P.; Goodwin, D.A.

    1982-12-01

    When polymorphonuclear leukocytes (PMNs) and mononuclear cells were isolated from the blood of dexamethasone-treated normal rats, in vitro mononuclear cell migration was inhibited and PMN migration was stimulated in comparison to controls. Inflammogen-induced PMNs showed inhibited cell migration due to dexamethasone treatment. Gamma camera imaging was then used to detect cells in vivo after labeling with /sup 111/In. When the dexamethasone-treated blood cells were injected into adjuvant arthritis diseased rats, mononuclear cells showed depressed migration into the inflamed paws, while PMNs showed stimulated migration into the inflamed paws in comparison to controls. When the recipient adjuvant arthritic animals were treated with dexamethasone, both normal mononuclear cell and normal PMN migration to the inflamed paws were inhibited.

  20. Ossicular Bone Damage and Hearing Loss in Rheumatoid Arthritis: A Correlated Functional and High Resolution Morphometric Study in Collagen-Induced Arthritic Mice

    PubMed Central

    Barbe, Mary F.

    2016-01-01

    Globally, a body of comparative case-control studies suggests that rheumatoid arthritis (RA) patients are more prone to developing hearing loss (HL). However, experimental evidence that supports this hypothesis is still lacking because the human auditory organ is not readily accessible. The aim of this study was to determine the association between bone damage to the ossicles of the middle ear and HL, using a widely accepted murine model of collagen-induced arthritis (RA mice). Diarthrodial joints in the middle ear were examined with microcomputer tomography (microCT), and hearing function was assessed by auditory brainstem response (ABR). RA mice exhibited significantly decreased hearing sensitivity compared to age-matched controls. Additionally, a significant narrowing of the incudostapedial joint space and an increase in the porosity of the stapes were observed. The absolute latencies of all ABR waves were prolonged, but mean interpeak latencies were not statistically different. The observed bone defects in the middle ear that were accompanied by changes in ABR responses were consistent with conductive HL. This combination suggests that conductive impairment is at least part of the etiology of RA-induced HL in a murine model. Whether the inner ear sustains bone erosion or other pathology, and whether the cochlear nerve sustains pathology await subsequent studies. Considering the fact that certain anti-inflammatories are ototoxic in high doses, monitoring RA patients’ auditory function is advisable as part of the effort to ensure their well-being. PMID:27690307

  1. Neuroplasticity of Sensory and Sympathetic Nerve Fibers in the Painful Arthritic Joint

    PubMed Central

    Ghilardi, Joseph R.; Freeman, Katie T.; Jimenez-Andrade, Juan M.; Coughlin, Kathleen; Kaczmarska, Magdalena J.; Castaneda-Corral, Gabriela; Bloom, Aaron P.; Kuskowski, Michael A.; Mantyh, Patrick W.

    2012-01-01

    Objective Many forms of arthritis are accompanied by significant chronic joint pain. Here we studied whether there is significant sprouting of sensory and sympathetic nerve fibers in the painful arthritic knee joint and whether nerve growth factor (NGF) drives this pathological reorganization. Methods A painful arthritic knee joint was produced by injection of complete Freund’s adjuvant (CFA) into the knee joint of young adult mice. CFA-injected mice were then treated systemically with vehicle or anti-NGF antibody. Pain behaviors were assessed and at 28 days following the initial CFA injection, the knee joints were processed for immunohistochemistry using antibodies raised against calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), growth associated protein-43 (GAP43; sprouted nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), CD31 (endothelial cells) or CD68 (monocytes/macrophages). Results In CFA-injected mice, but not vehicle-injected mice, there was a significant increase in the density of CD68+ macrophages, CD31+ blood vessels, CGRP+, NF200+, GAP43+, and TH+ nerve fibers in the synovium as well as joint pain-related behaviors. Administration of anti-NGF reduced these pain-related behaviors and the ectopic sprouting of nerve fibers, but had no significant effect on the increase in density of CD31+ blood vessels or CD68+ macrophages. Conclusions Ectopic sprouting of sensory and sympathetic nerve fibers occurs in the painful arthritic joint and may be involved in the generation and maintenance of arthritic pain. PMID:22246649

  2. Clinical Evaluation of the Efficacy of Arthocare Forte, a Chondro-Protective and Anti-Arthritic Drug in the Management of Bacterial Plaque-Induced Chronic Periodontitis

    PubMed Central

    Anyanechi, CE; Chukwuneke, FN; Ngim, N

    2015-01-01

    Background: Arthocare forte medication is made up of different constituents and the advantages offered by this disposition have not been explored in the management of chronic periodontitis. Aim: The aim was to assess the clinical response of bacterial plaque-induced generalized chronic periodontitis to arthocare medication, and the relationship of age and gender to the prevalence of chronic periodontal disease. Subjects and Methods: This study was done at the Dental Surgery Clinic of the University of Calabar Teaching Hospital, Nigeria. It was a Prospective randomized controlled trial evaluating the effect of arthocare treatment on 81/162 patients with teeth mobility over a period of 5 years. All the patients (162) underwent root planing, and 81/162 (50%) were treated with arthocare for comparative analysis. The variables recorded were patient's age, gender, and degree of tooth mobility, periodontal pocket, and bleeding from the pocket after treatment. Statistical analysis was done using EPI INFO 7. Results: Majority of the patients were between 46 and 75 years in both control (n = 59/81, 72.8%) and experimental groups (n = 52/81, 64.2%). There were 86/162 (53.1%) males and 76/162 (46.9%) females, giving a male-to-female ratio of 1.1:1. Seventy-seven patients (95.1%) in the experimental group had total remission in comparison to 32/81 (39.5%) in control group which was statistically significant (P < 0.001). Conclusion: The arthocare administered to patients in the experimental group speeds up the regenerative capacity and stability of the periodontium when compared with the control. Multicentre clinical trials are recommended to validate the use of arthocare forte in the treatment of generalized chronic periodontitis. PMID:26097755

  3. 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

  4. 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

  5. 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

  6. Penetration and effect of topically applied dimethylsulfoxide or indomethacin on adjuvant arthritis in the rat

    SciTech Connect

    Francis, M.D.; Horn, P.A.; McCreary, L.D.

    1983-07-01

    The present study, using /sup 14/C-DMSO, established the systemic and local load and distribution of topically applied DMSO in adjuvant arthritic rats. Under equivalent conditions, the antiinflammatory effects (systemic and local) of topical DMSO treatments were compared with a topical treatment of a control vehicle or of indomethacin, a known effective antiinflammatory agent. No significant systemic or local antiinflammatory effect of topical DMSO was seen in the adjuvant arthritic rats. Indomethacin, applied topically, had a significant systemic antiinflammatory effect; however, no significant local antiinflammatory effect of indomethacin was observed.

  7. 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.

  8. 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

  9. 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.

  10. [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.

  11. The Rheumatoid Arthritic At Home

    PubMed Central

    Hunt, T. E.

    1977-01-01

    Most management of rheumatoid arthritis must take place in the patient's own home with only intermittent professional help. With good planning and instruction it is possible to create in the home a milieu appropriate not only for possible inducement of remission, but also for continuing care during even protracted disability. The mainstay of treatment in all stages of this disease is the achievement of a right balance between rest and activity. In the initial stages, proper rest and support, including splinting of the joints with other simple measures, will greatly relieve pain and help control the inflammatory process. A variety of therapeutic exercises can reduce the likelihood of secondary immobility and promote restoration of strength and function. For the patient in whom the disease has become chronic and disabling a wide variety of self-help devices can be prescribed, together with appropriate home modifications. ImagesFig. 1Fig. 2Fig. 3Figs. 4 & 5Fig. 6Fig. 7 PMID:21307997

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  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. The surgical management of the arthritic hand.

    PubMed Central

    Harrison, S. H.

    1979-01-01

    The surgical management of the arthritic hand is very largely concerned with rheumatoid arthritis and Still's disease and less frequently with psoriatic and degenerative arthritis. In the rheumatoid hand the surgeon may be called upon to intervene at any point in the chain reaction leading to total deformity, performing synovectomies of joints or tendons to relieve pain or prevent further deformity, repairing ruptured tendons, restoring the mechanism of injured joints, and correcting deformities when they have been allowed to occur. The great variety of operations that may be necessary to achieve these ends, with varying degrees of success, are discussed with reference to a personal series of 970 cases and 2002 operations. Images FIG. 1 FIG. 2 FIG. 3 FIG. 4 FIG. 5 FIG. 7 FIG. 6 FIG. 8 PMID:420491

  2. 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

  3. Bacopa monniera (L.) wettst inhibits type II collagen-induced arthritis in rats.

    PubMed

    Viji, V; Kavitha, S K; Helen, A

    2010-09-01

    Bacopa monniera (L.) Wettst is an Ayurvedic herb with antirheumatic potential. This study investigated the therapeutic efficacy of Bacopa monniera in treating rheumatoid arthritis using a type II collagen-induced arthritis rat model. Arthritis was induced in male Wistar rats by immunization with bovine type II collagen in complete Freund's adjuvant. Bacopa monniera extract (BME) was administered after the development of arthritis from day 14 onwards. The total duration of experiment was 60 days. Paw swelling, arthritic index, inflammatory mediators such as cyclooxygenase, lipoxygenase, myeloperoxidase and serum anti-collagen IgG and IgM levels were analysed in control and experimental rats. Arthritic induction significantly increased paw edema and other classical signs of arthritis coupled to upregulation of inflammatory mediators such as cyclooxygenase, lipoxygenase, neutrophil infiltration and increased anti-collagen IgM and IgG levels in serum. BME significantly inhibited the footpad swelling and arthritic symptoms. BME was effective in inhibiting cyclooxygenase and lipoxygenase activities in arthritic rats. Decreased neutrophil infiltration was evident from decreased myeloperoxidase activity and histopathological data where an improvement in joint architecture was also observed. Serum anti-collagen IgM and IgG levels were consistently decreased. Thus the study demonstrates the potential antiarthritic effect of Bacopa monniera for treating arthritis which might confer its antirheumatic activity.

  4. Alterations to the middle cerebral artery of the hypertensive-arthritic rat model potentiates intracerebral hemorrhage

    PubMed Central

    Chokshi, Killol; Kane, Brittany; Chang, Hilary; Naiel, Safaa; Dickhout, Jeffrey G.

    2016-01-01

    Aims We have recently created an age-dependent hypertensive-mono-arthritic animal model from the stroke-resistant spontaneously hypertensive rat to model populations with autoimmune disease who are hypertensive and are prone to stroke. The model exhibits signs of hemorrhagic stroke (HS) subsequent to chronic inflammation and hypertension. HS is also associated with the inability of middle cerebral arteries to undergo pressure dependent constriction (PDC). We investigated alterations in the cerebrovasculature of our hypertensive mono-arthritic animals that develop stroke. Main Methods Animals were fed either a high salt diet (HSD) (4% NaCl) or Purina chow (0.58% NaCl) from weaning. Complete Freund’s Adjuvant (CFA) was injected into the left hind paw at 21–28 weeks; controls received saline and histological and functional studies were performed. Results Brain damage was more prominent with the high salt, with inflammation exacerbating the damage. High salt alone significantly decreased middle cerebral artery’s (MCA’s) ability to undergo PDC. Inflammation significantly decreased the ability of cerebrovasculature to respond to pressure step in the regular salt diet. The responses to vasoactive peptides were also significantly attenuated in both inflamed groups regardless of diet. Conclusion Induction of chronic systemic inflammation increases brain damage, and affect the MCA’s vasogenic function, decreasing its ability to respond to intraluminal pressure. HSD further exacerbates organ damage associated with chronic inflammation, further compromising cerebrovascular function, and likely increasing the incidence of intracerebral hemorrhage and injury. PMID:27833798

  5. Anti-arthritic effects and toxicity of the essential oils of turmeric (Curcuma longa L.).

    PubMed

    Funk, Janet L; Frye, Jennifer B; Oyarzo, Janice N; Zhang, Huaping; Timmermann, Barbara N

    2010-01-27

    Turmeric (Curcuma longa L., Zingiberaceae) rhizomes contain two classes of secondary metabolites, curcuminoids and the less well-studied essential oils. Having previously identified potent anti-arthritic effects of the curcuminoids in turmeric extracts in an animal model of rheumatoid arthritis (RA), studies were undertaken to determine whether the turmeric essential oils (TEO) were also joint protective using the same experimental model. Crude or refined TEO extracts dramatically inhibited joint swelling (90-100% inhibition) in female rats with streptococcal cell wall (SCW)-induced arthritis when extracts were administered via intraperitoneal injection to maximize uniform delivery. However, this anti-arthritic effect was accompanied by significant morbidity and mortality. Oral administration of a 20-fold higher dose TEO was nontoxic, but only mildly joint-protective (20% inhibition). These results do not support the isolated use of TEO for arthritis treatment but, instead, identify potential safety concerns in vertebrates exposed to TEO.

  6. 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.

  7. 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

  8. 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.

  9. Targeting of viral interleukin-10 with an antibody fragment specific to damaged arthritic cartilage improves its therapeutic potency

    PubMed Central

    2014-01-01

    Introduction We previously demonstrated that a single-chain fragment variable (scFv) specific to collagen type II (CII) posttranslationally modified by reactive oxygen species (ROS) can be used to target anti-inflammatory therapeutics specifically to inflamed arthritic joints. The objective of the present study was to demonstrate the superior efficacy of anti-inflammatory cytokines when targeted to inflamed arthritic joints by the anti-ROS modified CII (anti-ROS-CII) scFv in a mouse model of arthritis. Methods Viral interleukin-10 (vIL-10) was fused to anti-ROS-CII scFv (1-11E) with a matrix-metalloproteinase (MMP) cleavable linker to create 1-11E/vIL-10 fusion. Binding of 1-11E/vIL-10 to ROS-CII was determined by enzyme-linked immunosorbent assay (ELISA), Western blotting, and immune-staining of arthritic cartilage, whereas vIL-10 bioactivity was evaluated in vitro by using an MC-9 cell-proliferation assay. Specific in vivo localization and therapeutic efficacy of 1-11E/vIL-10 was tested in the mouse model of antigen-induced arthritis. Results 1-11E/vIL-10 bound specifically to ROS-CII and to damaged arthritic cartilage. Interestingly, the in vitro vIL-10 activity in the fusion protein was observed only after cleavage with MMP-1. When systemically administered to arthritic mice, 1-11E/vIL-10 localized specifically to the arthritic knee, with peak accumulation observed after 3 days. Moreover, 1-11E/vIL-10 reduced inflammation significantly quicker than vIL-10 fused to the control anti-hen egg lysozyme scFv (C7/vIL10). Conclusions Targeted delivery of anti-inflammatory cytokines potentiates their anti-arthritic action in a mouse model of arthritis. Our results further support the hypothesis that targeting biotherapeutics to arthritic joints may be extended to include anti-inflammatory cytokines that lack efficacy when administered systemically. PMID:25029910

  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. Small cationic DDA:TDB liposomes as protein vaccine adjuvants obviate the need for TLR agonists in inducing cellular and humoral responses.

    PubMed

    Milicic, Anita; Kaur, Randip; Reyes-Sandoval, Arturo; Tang, Choon-Kit; Honeycutt, Jared; Perrie, Yvonne; Hill, Adrian V S

    2012-01-01

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

  12. Anti-inflammatory and anti-arthritic effects of Yucca schidigera: a review.

    PubMed

    Cheeke, P R; Piacente, S; Oleszek, W

    2006-03-29

    Yucca schidigera is a medicinal plant native to Mexico. According to folk medicine, yucca extracts have anti-arthritic and anti-inflammatory effects. The plant contains several physiologically active phytochemicals. It is a rich source of steroidal saponins, and is used commercially as a saponin source. Saponins have diverse biological effects, including anti-protozoal activity. It has been postulated that saponins may have anti-arthritic properties by suppressing intestinal protozoa which may have a role in joint inflammation. Yucca is also a rich source of polyphenolics, including resveratrol and a number of other stilbenes (yuccaols A, B, C, D and E). These phenolics have anti-inflammatory activity. They are inhibitors of the nuclear transcription factor NFkappaB. NFkB stimulates synthesis of inducible nitric oxide synthase (iNOS), which causes formation of the inflammatory agent nitric oxide. Yucca phenolics are also anti-oxidants and free-radical scavengers, which may aid in suppressing reactive oxygen species that stimulate inflammatory responses. Based on these findings, further studies on the anti-arthritic effects of Yucca schidigera are warranted.

  13. Anti-inflammatory and anti-arthritic effects of yucca schidigera: A review

    PubMed Central

    Cheeke, PR; Piacente, S; Oleszek, W

    2006-01-01

    Yucca schidigera is a medicinal plant native to Mexico. According to folk medicine, yucca extracts have anti-arthritic and anti-inflammatory effects. The plant contains several physiologically active phytochemicals. It is a rich source of steroidal saponins, and is used commercially as a saponin source. Saponins have diverse biological effects, including anti-protozoal activity. It has been postulated that saponins may have anti-arthritic properties by suppressing intestinal protozoa which may have a role in joint inflammation. Yucca is also a rich source of polyphenolics, including resveratrol and a number of other stilbenes (yuccaols A, B, C, D and E). These phenolics have anti-inflammatory activity. They are inhibitors of the nuclear transcription factor NFkappaB. NFkB stimulates synthesis of inducible nitric oxide synthase (iNOS), which causes formation of the inflammatory agent nitric oxide. Yucca phenolics are also anti-oxidants and free-radical scavengers, which may aid in suppressing reactive oxygen species that stimulate inflammatory responses. Based on these findings, further studies on the anti-arthritic effects of Yucca schidigera are warranted. PMID:16571135

  14. Characterization and treatment monitoring of inflammatory arthritis by photoacoustic imaging: a study on adjuvant-induced arthritis rat model

    NASA Astrophysics Data System (ADS)

    Wang, Xueding; Rajian, Justin; Shao, Xia; Chamberland, David L.; Girish, Gandikota

    2014-03-01

    Neovascularity also known as angiogenesis is an early feature of inflammatory arthritis disease. Therefore, identifying the development of neovascularity is one way to potentially detect and characterize arthritis. Laser-based photoacoustic imaging (PAI) is an emerging biomedical imaging modality which may aid in detection of both early and continued development of neovascularity. In this work, we investigated the feasibility of PAI to measure angiogenesis, for the purpose of evaluating and monitoring inflammatory arthritis after treatment. The imaging results on an arthritis rat model demonstrate that 1) there is noticeable enhancement in image intensity in the arthritic ankle joints when compared to the normal joints, and 2) there is noticeable decrease in image intensity in the arthritic ankle joints after treatment when compared to the untreated arthritic joints. In order to validate the findings from PAI, we performed positron emission tomography (PET) and histology on the same joints. The diameters of the ankle joints, as a clinical score of the arthritis, were also measured at each time point.

  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. Inhibition of LPS-induced TNF-α and NO production in mouse macrophage and inflammatory response in rat animal models by a novel Ayurvedic formulation, BV-9238.

    PubMed

    Dey, Debendranath; Chaskar, Sunetra; Athavale, Nitin; Chitre, Deepa

    2014-10-01

    Rheumatoid arthritis is a chronic crippling disease, where protein-based tumor necrosis factor-alpha (TNF-α) inhibitors show significant relief, but with potentially fatal side effects. A need for a safe, oral, cost-effective small molecule or phyto-pharmaceutical is warranted. BV-9238 is an Ayurvedic poly-herbal formulation containing specialized standardized extracts of Withania somnifera, Boswellia serrata, Zingiber officinale and Curcuma longa. The anti-inflammatory and anti-arthritic effects of BV-9238 were evaluated for inhibition of TNF-α and nitric oxide (NO) production, in lipopolysaccharide-stimulated, RAW 264.7, mouse macrophage cell line. BV-9238 reduced TNF-α and NO production, without any cytotoxic effects. Subsequently, the formulation was tested in adjuvant-induced arthritis (AIA) and carrageenan-induced paw edema (CPE) rat animal models. AIA was induced in rats by injecting Freund's complete adjuvant intra-dermally in the paw, and BV-9238 and controls were administered orally for 21 days. Arthritic scores in AIA study and inflamed paw volume in CPE study were significantly reduced upon treatment with BV-9238. These results suggest that the anti-inflammatory and anti-arthritic effects of BV-9238 are due to its inhibition of TNF-α, and NO, and this formulation shows promise as an alternate therapy for inflammatory disorders where TNF-α and NO play important roles.

  17. 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.

  18. 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.

  19. 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

  20. Enhancing Methotrexate Tolerance with Folate Tagged Liposomes in Arthritic Mice.

    PubMed

    Nogueira, Eugénia; Lager, Franck; Le Roux, Delphine; Nogueira, Patrícia; Freitas, Jaime; Charvet, Celine; Renault, Gilles; Loureiro, Ana; Almeida, Catarina R; Ohradanova-Repic, Anna; Machacek, Christian; Bernardes, Gonçalo J L; Moreira, Alexandra; Stockinger, Hannes; Burnet, Michael; Carmo, Alexandre M; Gomes, Andreia C; Preto, Ana; Bismuth, Georges; Cavaco-Paulo, Artur

    2015-12-01

    Methotrexate is the first line of treatment of rheumatoid arthritis. Since many patients become unresponsive to methotrexate treatment, only very expensive biological therapies are effective and increased methotrexate tolerance strategies need to be identified. Here we propose the encapsulation of methotrexate in a new liposomal formulation using a hydrophobic fragment of surfactant protein conjugated to a linker and folate to enhance their tolerance and efficacy. In this study we aim to evaluate the efficiency of this system to treat rheumatoid arthritis, by targeting folate receptor β present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor β was investigated both in vitro as in vivo using a mouse model of arthritis (collagen-induced arthritis in DBA/1J mice strain). In both systems, the liposomal constructs were shown to be highly specific and efficient in targeting folate receptor β. These liposomal formulations also significantly increase the clinical benefit of the encapsulated methotrexate in vivo in arthritic mice, together with reduced expression of CD39 and CD73 ectonucleotidases by joint-infiltrating macrophages. Thus, our formulation might be a promising cost effective way to treat rheumatoid arthritis and delay or reduce methotrexate intolerance.

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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

  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. 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.

  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. 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

  11. 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.

  12. 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".

  13. Identification of inflammation sites in arthritic joints using hyperspectral imaging

    NASA Astrophysics Data System (ADS)

    Paluchowski, Lukasz A.; Milanic, Matija; Bjorgan, Asgeir; Grandaunet, Berit; Dhainaut, Alvilde; Hoff, Mari; Randeberg, Lise L.

    2014-03-01

    Inflammatory arthritic diseases have prevalence between 2 and 3% and may lead to joint destruction and deformation resulting in a loss of function. Patient's quality of life is often severely affected as the disease attacks hands and finger joints. Pathology involved in arthritis includes angiogenesis, hyper-vascularization, hyper-metabolism and relative hypoxia. We have employed hyperspectral imaging to study the hemodynamics of affected- and non-affected joints and tissue. Two hyperspectral, push-broom cameras were used (VNIR-1600, SWIR-320i, Norsk Elektro Optikk AS, Norway). Optical spectra (400nm - 1700nm) of high spectral resolution were collected from 15 patients with visible symptoms of arthritic rheumatic diseases in at least one joint. The control group consisted of 10 healthy individuals. Concentrations of dominant chromophores were calculated based on analytical calculations of light transport in tissue. Image processing was used to analyze hyperspectral data and retrieve information, e.g. blood concentration and tissue oxygenation maps. The obtained results indicate that hyperspectral imaging can be used to quantify changes within affected joints and surrounding tissue. Further improvement of this method will have positive impact on diagnosis of arthritic joints at an early stage. Moreover it will enable development of fast, noninvasive and noncontact diagnostic tool of arthritic joints

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. 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

  20. Up-regulation of prostaglandin E receptor EP2 and EP4 subtypes in rat synovial tissues with adjuvant arthritis

    PubMed Central

    Kurihara, Y; Endo, H; Akahoshi, T; Kondo, H

    2001-01-01

    To evaluate the role of the prostaglandin E receptor (EP) subtypes in the development of inflammatory synovitis, we examined EP subtype mRNA distribution in the synovial tissue of rats with adjuvant arthritis and the effect of selective EP agonists on cytokine production by cultured rat synovial cells. We used reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization to measure the level of EP subtype (EP1, EP2, EP3, and EP4) mRNA expression in synovial tissues and cultured synovial cells from the arthritic joints of rats. RT-PCR and ELISA were used to analyse the effects of two selective EP agonists on IL-6 production by cultured rat synovial cells. EP2 and EP4 mRNA expression in inflamed synovial tissues was up-regulated. EP2 and EP4 mRNA were co-expressed in synovial macrophages and fibroblasts in inflamed tissues. EP4 and EP2 agonists both inhibited IL-1-induced IL-6 production. Our results suggest that prostaglandin E2 regulates the functions of synovial macrophages and fibroblasts through EP2 and EP4, which are induced by inflammatory stimuli in rats with adjuvant arthritis. PMID:11207665

  1. Up-regulation of prostaglandin E receptor EP2 and EP4 subtypes in rat synovial tissues with adjuvant arthritis.

    PubMed

    Kurihara, Y; Endo, H; Akahoshi, T; Kondo, H

    2001-02-01

    To evaluate the role of the prostaglandin E receptor (EP) subtypes in the development of inflammatory synovitis, we examined EP subtype mRNA distribution in the synovial tissue of rats with adjuvant arthritis and the effect of selective EP agonists on cytokine production by cultured rat synovial cells. We used reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization to measure the level of EP subtype (EP1, EP2, EP3, and EP4) mRNA expression in synovial tissues and cultured synovial cells from the arthritic joints of rats. RT-PCR and ELISA were used to analyse the effects of two selective EP agonists on IL-6 production by cultured rat synovial cells. EP2 and EP4 mRNA expression in inflamed synovial tissues was up-regulated. EP2 and EP4 mRNA were co-expressed in synovial macrophages and fibroblasts in inflamed tissues. EP4 and EP2 agonists both inhibited IL-1-induced IL-6 production. Our results suggest that prostaglandin E2 regulates the functions of synovial macrophages and fibroblasts through EP2 and EP4, which are induced by inflammatory stimuli in rats with adjuvant arthritis.

  2. Time course of antibodies against IgG and type II collagen in adjuvant arthritis. Role of mycobacteria administration in antibody production.

    PubMed

    Franch, A; Cassany, S; Castellote, C; Castell, M

    1994-02-01

    The aim of this study was to elucidate, during the time course of adjuvant arthritis, the existence of antibodies directed to IgG (rheumatoid factor-like) and antibodies against type II collagen. In a second study, we also studied the relation between antibody production, arthritic process and mycobacteria administration. We have demonstrated the presence of antibodies to IgG and type II collagen by means of ELISA techniques. This reactivity appeared on day 7 post-induction, decreased later, and increased progressively from day 21 until last day studied (day 56 post-induction). We have also quantified antibodies against a soluble fraction of Mycobacterium butyricum, the inductor of the disease. Anti-mycobacteria antibodies appeared during the first seven days after induction, but from day 14, when systemic inflammation began, their levels suddenly increased. There is a positive correlation between anti-mycobacteria antibody levels and articular swelling. Anti-IgG and anti-collagen antibody production was not directly linked to arthritic process since these antibodies were synthesized when M. butyricum was administered intraperitoneally, which does not induce arthritis. Anti-mycobacteria antibody concentration was higher when arthritis induction by mycobacterial was successful than when it was unsuccessful.

  3. 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

  4. 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

  5. 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.

  6. Simulation of light transport in arthritic- and non-arthritic human fingers

    NASA Astrophysics Data System (ADS)

    Milanic, Matija; Paluchowski, Lukasz A.; Randeberg, Lise L.

    2014-03-01

    Rheumatoid arthritis is a disease that frequently leads to joint destruction. It has high incidence rates worldwide, and the disease significantly reduces patient's quality of life due to pain, swelling and stiffness of the affected joints. Early diagnosis is necessary to improve course of the disease, therefore sensitive and accurate diagnostic tools are required. Optical imaging techniques have capability for early diagnosis and monitoring of arthritis. As compared to conventional diagnostic techniques optical technique is a noninvasive, noncontact and fast way of collecting diagnostic information. However, a realistic model of light transport in human joints is needed for understanding and developing of such optical diagnostic tools. The aim of this study is to develop a 3D numerical model of light transport in a human finger. The model will guide development of a hyperspectral imaging (HSI) diagnostic modality for arthritis in human fingers. The implemented human finger geometry is based on anatomical data. Optical data of finger tissues are adjusted to represent either an arthritic or an unaffected finger. The geometry and optical data serve as input into a 3D Monte Carlo method, which calculate diffuse reflectance, transmittance and absorbed energy distributions. The parameters of the model are optimized based on HIS-measurements of human fingers. The presented model serves as an important tool for understanding and development of HSI as an arthritis diagnostic modality. Yet, it can be applied to other optical techniques and finger diseases.

  7. Saposin C coupled lipid nanovesicles specifically target arthritic mouse joints for optical imaging of disease severity.

    PubMed

    Qi, Xiaoyang; Flick, Matthew J; Frederick, Malinda; Chu, Zhengtao; Mason, Rachel; DeLay, Monica; Thornton, Sherry

    2012-01-01

    Rheumatoid arthritis is a chronic inflammatory disease affecting approximately 1% of the population and is characterized by cartilage and bone destruction ultimately leading to loss of joint function. Early detection and intervention of disease provides the best hope for successful treatment and preservation of joint mobility and function. Reliable and non-invasive techniques that accurately measure arthritic disease onset and progression are lacking. We recently developed a novel agent, SapC-DOPS, which is composed of the membrane-associated lysosomal protein saposin C (SapC) incorporated into 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) lipid nanovesicles. SapC-DOPS has a high fusogenic affinity for phosphatidylserine-enriched microdomains on surfaces of target cell membranes. Incorporation of a far-red fluorophore, CellVue Maroon (CVM), into the nanovesicles allows for in vivo non-invasive visualization of the agent in targeted tissue. Given that phosphatidylserine is present only on the inner leaflet of healthy plasma membranes but is "flipped" to the outer leaflet upon cell damage, we hypothesized that SapC-DOPS would target tissue damage associated with inflammatory arthritis due to local surface-exposure of phosphatidylserine. Optical imaging with SapC-DOPS-CVM in two distinct models of arthritis, serum-transfer arthritis (e.g., K/BxN) and collagen-induced arthritis (CIA) revealed robust SapC-DOPS-CVM specific localization to arthritic paws and joints in live animals. Importantly, intensity of localized fluorescent signal correlated with macroscopic arthritic disease severity and increased with disease progression. Flow cytometry of cells extracted from arthritic joints demonstrated that SapC-DOPS-CVM localized to an average of 7-8% of total joint cells and primarily to CD11b+Gr-1+ cells. Results from the current studies strongly support the application of SapC-DOPS-CVM for advanced clinical and research applications including: detecting early arthritis

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. Cationic liposomes as vaccine adjuvants.

    PubMed

    Christensen, Dennis; Korsholm, Karen Smith; Andersen, Peter; Agger, Else Marie

    2011-04-01

    The application of cationic liposomes as vaccine delivery systems and adjuvants has been investigated extensively over the last few decades. However, cationic liposomes are, in general, not sufficiently immunostimulatory, which is why the combination of liposomes with immunostimulating ligands has arisen as a strategy in the development of novel adjuvant systems. Within the last 5 years, two novel adjuvant systems based on cationic liposomes incorporating Toll-like receptor or non-Toll-like receptor immunostimulating ligands have progressed from preclinical testing in smaller animal species to clinical testing in humans. The immune responses that these clinical candidates induce are primarily of the Th1 type for which there is a profound unmet need. Furthermore, a number of new cationic liposome-forming surfactants with notable immunostimulatory properties have been discovered. In this article we review the recent progress on the application of cationic liposomes as vaccine delivery systems/adjuvants.

  14. 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

  15. 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

  16. 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.

  17. Adjuvant properties of a biocompatible thermo-responsive polymer of N-isopropylacrylamide in autoimmunity and arthritis

    PubMed Central

    Shakya, Akhilesh Kumar; Kumar, Ashok; Nandakumar, Kutty Selva

    2011-01-01

    To evaluate the thermo-responsive poly(N-isopropylacrylamide) (PNiPAAm) polymer as an adjuvant, we synthesized PNiPAAm through free radical polymerization and characterized it both in vitro and in vivo. The polymer when mixed with collagen type II (CII) induced antigen-specific autoimmunity and arthritis. Mice immunized with PNiPAAm–CII developed significant levels of CII-specific IgG response comprising major IgG subclasses. Antigen-specific cellular recall response was also enhanced in these mice, while negligible level of IFN-γ was detected in splenocyte cultures, in vitro. PNiPAAm–CII-immunized arthritic mouse paws showed massive infiltration of immune cells and extensive damage to cartilage and bone. As determined by immunostaining, most of the CII protein retained its native configuration after injecting it with PNiPAAm in naive mice. Physical adsorption of CII and the high-molecular-weight form of moderately hydrophobic PNiPAAm induced a significant anti-CII antibody response. Similar to CII, mice immunized with PNiPAAm and ovalbumin (PNiPAAm–Ova) induced significant anti-ovalbumin antibody response. Comparable levels of serum IFN-γ, IL-1β and IL-17 were observed in ovalbumin-immunized mice with complete Freund, incomplete Freund (CFA and IFA) or PNiPAAm adjuvants. However, serum IL-4 levels were significantly higher in PNiPAAm–Ova and CFA–Ova groups compared with the IFA–Ova group. Thus, we show for the first time, biocompatible and biodegradable thermo-responsive PNiPAAm can be used as an adjuvant in several immunological applications as well as in better understanding of the autoimmune responses against self-proteins. PMID:21543351

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. Periarticular osteopenia in adjuvant induced arthritis: role of interleukin-1 in decreased osteogenic and increased resorptive potential of bone marrow cells.

    PubMed Central

    Suzuki, Y; Tanihara, M; Ichikawa, Y; Osanai, A; Nakagawa, M; Ide, M; Mizushima, Y

    1995-01-01

    OBJECTIVE--To clarify the local osteogenic and bone resorptive potential of periarticular bone in adjuvant induced arthritis (AIA). METHODS--Formation of fibroblast colony forming units (FCFU; osteogenic precursor cells) and osteoclast-like cells in bone marrow culture was studied in AIA rats. Osteoclast-inducing activity in the AIA rat bone marrow was assayed by the addition of the marrow supernatant from rats with AIA to control cultures. Bone mineral density was determined by dual x ray absorptiometry. RESULTS--Marrow from AIA rats and that from animals receiving recombinant human interleukin-1 (IL-1) beta for seven days grew significantly fewer FCFU than control marrow. Formation of osteoclast-like cells was increased in bone marrow cultures from rats with AIA, especially when bone marrow cells were cultured in the presence of marrow supernatant. Formation of resorption lacunae on ivory slices was increased in the marrow cultures from rats with AIA, especially from the right (adjuvant inoculated) tibia. AIA rat marrow supernatant promoted osteoclast-like cell formation in control culture, and this was significantly suppressed by an anti-IL-1 antibody. Rats with AIA showed a significant decrease in the bone mineral density of the periarticular regions of the tibia and femur. CONCLUSION--An uncoupled state in bone resorption-formation linkage, possibly mediated through an increase of IL-1 in the bone marrow, may contribute to the development of periarticular osteopenia in inflammatory arthritis. Images PMID:7632091

  10. 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

  11. Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) isolated from Boesenbergia rotunda (L.) Mansf. inhibits CFA-induced rheumatoid arthritis in rats.

    PubMed

    Voon, Fui-Ling; Sulaiman, Mohd Roslan; Akhtar, Muhammad Nadeem; Idris, Mohamad Fauzi; Akira, Ahmad; Perimal, Enoch Kumar; Israf, Daud Ahmad; Ming-Tatt, Lee

    2017-01-05

    Boesenbergia rotunda (L.) Mansf. had been traditionally used as herbs to treat pain and rheumatism. Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) is a compound isolated from Boesenbergia rotunda (L.) Mansf.. Previous study had shown the potential of cardamonin in inhibiting the release of pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in vitro. Thus, the possible therapeutic effect of cardamonin in the rheumatoid arthritis (RA) joints is postulated. This study was performed to investigate the anti-arthritic properties of cardamonin in rat model of induced RA, particularly on the inflammatory and pain response of RA. Rheumatoid arthritis paw inflammation was induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA) in Sprague Dawley rats. Using four doses of cardamonin (0.625, 1.25, 2.5, and 5.0mg/kg), anti-arthritic activity was evaluated through the paw edema, mechanical allodynia and thermal hyperalgesia responses. Enzyme-linked immunosorbent assay (ELISA) was carried out to evaluate the plasma level of TNF-α, IL-1β, and IL-6. Histological slides were prepared from the harvested rat paws to observe the arthritic changes in the joints. Behavioral, biochemical, and histological studies showed that cardamonin demonstrated significant inhibition on RA-induced inflammatory and pain responses as well as progression of joint destruction in rats. ELISA results showed that there was significant inhibition in TNF-α, IL-1β, and IL-6 levels in plasma of the cardamonin-treated RA rats. Overall, cardamonin possesses potential anti-arthritic properties in CFA-induced RA rat model.

  12. 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

  13. 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.

  14. A LC-ESI-MS method for the simultaneous determination of madecassoside and its metabolite madecassic acid in rat plasma: comparison pharmacokinetics in normal and collagen-induced arthritic rats.

    PubMed

    Wang, Ting; Leng, Dan-Dan; Gao, Fei-Fei; Jiang, Chun-Jie; Xia, Yu-Feng; Dai, Yue

    2014-12-01

    To develop a simple and highly sensitive high performance liquid chromatography with electrospray ionization mass spectrometric (LC-ESI-MS) method for the simultaneous determination of madecassoside and its major metabolite madecassic acid in rat plasma, and compare the pharmacokinetics of the two compounds in normal and collagen-induced arthritis (CIA) rats. Glycyrrhetinic acid was used as the internal standard (IS). Chromatographic separation was accomplished on an Inertsil ODS-3 column, using a gradient elution with the mobile phase composed of acetonitrile and water acidified with 0.1% (V/V) formic acid. Detection was achieved by ESI-MS under the negative selected ion monitoring (SIM) mode. In normal and CIA rats, madecassoside (30 mg·kg(-1)) was orally administered for 21 consecutive days from the day of arthritis onset. For madecassoside, the linear range was 10-1 000 ng·mL(-1) with the square regression coefficient (r) of 0.998 9, while for madecassic acid, the linear range was 10-500 ng·mL(-1) with the square regression coefficient (r) of 0.996 1. The lower limit of quantification was 10 ng·mL(-1) for both analytes. The intra- and inter-day precision ranged from 1.78% to 13.42% for madecassoside and 2.30% to 14.90% for madecassic acid, and the accuracy was between -0.95% and 6.30% for madecassoside and between -1.48% and 5.34% for madecassic acid. The average recoveries of madecassoside, madecassic acid and IS from spiked plasma samples were > 81%. The developed method was successfully applied to the pharmacokinetic study of madecassoside and madecassic acid in rats after an oral administration of madecassoside. During initial 7 days of dosing, the cmax and AUC of madecassoside were greatly decreased and Vd/F was markedly increased in CIA rats, and no significant difference was observed on the first day of dosing. In contrast, the T1/2, cmax and AUC of madecassic acid were significantly increased, and Ke of madecassic acid was greatly decreased in CIA

  15. Efficacy of ultrasound mediated microbubbles in diclofenac gel to enhance transdermal permeation in rheumatoid arthritis induced rat.

    PubMed

    Liao, A H; Chuang, H C; Chung, H Y

    2015-08-01

    In previous study in the literature, the effect of ultrasound on the transdermal permeation of the nonsteroidal anti-inflammatory drug, diclofenac has been investigated. Therapeutic ultrasound can increase circulation in the inflamed joint and decrease arthritic pain. Recently, transdermal drug delivery has been demonstrated by ultrasound (US) combining with microbubbles (MBs) contrast agent. In this study, the efficiency of US-MBs mediated diclofenac delivery for adjuvant-induced rheumatoid arthritis (RA) in rats was evaluated. RA was induced by injection of 100 μl Freund's complete adjuvant into the ankle joint in SD male rats (250-300g) and were randomly divided into five groups: (1) control group (C); (2) penetrating diclofenac alone (D); (3) US alone (U); (4) US combined with penetrating diclofenac (DU); (5) US combined with MBs and penetrating diclofenac (DUB). The evaluations of ankle width were performed for 10 days by high frequency (40MHz) US B-mode and color Doppler mode imaging before and after treatment. Longitudinal US images of arthritis induced show synovitis and neovascularity. After treatment, only a little neovascularity has been observed. The recovery rate at 10th day in the group DUB (97.7±2.7 %) was significantly higher than in the group C (1.0±2.7 %), group D (37.5±4.6 %), group U (75.5±4.2 %) and group DU (87.3±5.2 %) (p <; 0.05). Our results investigated that the treatments of US and MBs can increase skin permeability to enhance diclofenac sodium delivery and inhibit inflammation of the tissues surrounded the arthritic ankle. In color Doppler imaging, after the combination treatment, the synovial neoangiogenesis in the arthritic area was reduced quickly.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. Sensory and sympathetic nerve fibers undergo sprouting and neuroma formation in the painful arthritic joint of geriatric mice

    PubMed Central

    2012-01-01

    Introduction Although the prevalence of arthritis dramatically increases with age, the great majority of preclinical studies concerning the mechanisms that drive arthritic joint pain have been performed in young animals. One mechanism hypothesized to contribute to arthritic pain is ectopic nerve sprouting; however, neuroplasticity is generally thought to be greater in young versus old nerves. Here we explore whether sensory and sympathetic nerve fibers can undergo a significant ectopic nerve remodeling in the painful arthritic knee joint of geriatric mice. Methods Vehicle (saline) or complete Freund's adjuvant (CFA) was injected into the knee joint of 27- to 29-month-old female mice. Pain behaviors, macrophage infiltration, neovascularization, and the sprouting of sensory and sympathetic nerve fibers were then assessed 28 days later, when significant knee-joint pain was present. Knee joints were processed for immunohistochemistry by using antibodies raised against CD68 (monocytes/macrophages), PECAM (endothelial cells), calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), and growth-associated protein 43 (GAP43; nerve fibers undergoing sprouting). Results At 4 weeks after initial injection, CFA-injected mice displayed robust pain-related behaviors (which included flinching, guarding, impaired limb use, and reduced weight bearing), whereas animals injected with vehicle alone displayed no significant pain-related behaviors. Similarly, in the CFA-injected knee joint, but not in the vehicle-injected knee joint, a remarkable increase was noted in the number of CD68+ macrophages, density of PECAM+ blood vessels, and density and formation of neuroma-like structures by CGRP+, NF200+, and TH+ nerve fibers in the synovium and periosteum. Conclusions Sensory and sympathetic nerve fibers that innervate the aged knee joint clearly maintain the capacity for robust

  4. 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

  5. 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.

  6. High-Methionine Diet Attenuates Severity of Arthritis and Modulates IGF-I Related Gene Expressions in an Adjuvant Arthritis Rats Model

    PubMed Central

    2016-01-01

    Rheumatoid arthritis, a synthesized form of adjuvant arthritis exhibited throughout many animal species, inhibits liver function and circulation of IGF-I and contributes to the degradation of skeletal muscle mass. One of the primary goals of the present study is determining whether a high-Methionine (high-Met) diet is capable of reducing the adverse effects of arthritis, namely, loss of body mass. Following adjuvant injection, forty arthritic rats were randomly assigned to either a control group with a basal diet or a high-Met group with the same basal diet + 0.5% Methionine. After 14 days all rats were terminated. The high-Met group exhibited an increase in body weight and food intake in comparison with the control group (P < 0.05). High-Met diet debilitated arthritis-induced surges in the gastrocnemius in both atrogin-1 and the MuRF1 expressions; however, it was observed to have little to no effect on atrogin-1 and MuRF1 gene expression in soleus. At the same time, high-Met diet rats experienced a rise in IGF-I, with lowering of IGFBP-3 gene expression in the gastrocnemius and the soleus. These data suggest that arthritis severity can be partly attenuated by high-Met diet. PMID:27738392

  7. 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.

  8. Arthrite à pneumocoque chez un adulte immunocompétent

    PubMed Central

    Chemsi, Hicham; Chadli, Maryama; Sekhsokh, Yassine

    2015-01-01

    Les infections à pneumocoques sont avant tout respiratoires, ORL et méningées. Les infections ostéoarticulaires à pneumocoque ont la particularité de survenir dans moins de 20% des cas chez l'adulte sain. Habituellement, un ou plusieurs facteurs favorisants sont retrouvés. Toutefois, nous rapportons lors de cette observation le cas d'une arthrite à Streptococcus pneumoniae chez un adulte immunocompétent sans facteurs prédisposant. Patient âgé de 66 ans, diabétique de type II, a été hospitalisé pour une décompensation acido-cétosique et une monoarthrite du genou droit. Ce patient était fébrile (39°C) et présentait un genou droit inflammatoire en flexion avec rougeur et chaleur locale et un choc rotulien. Une ponction articulaire avec d'autres examens ont été réalisés pour confirmation d'une arthrite septique à pneumocoque. Le résultat de la ponction articulaire réalisée a montré un liquide jaune citron trouble avec 480 000 leucocytes/mm3 à prédominance polynucléaires neutrophiles. L'examen direct a montré des coccis à Gram positif en diplocoque, la culture a permis d'isoler un Streptococcus pneumoniae sensible à la pénicilline G. L’évolution clinique et biologique de l'arthrite du genou était favorable. Un déficit immunitaire, un asplénisme anatomique ou fonctionnel peuvent être en cause. L'alcoolisme est un facteur favorisant mais le mécanisme n'est pas clairement élucidé. La présence de matériel prothétique, peut favoriser une localisation septique. Ces facteurs de risque doivent être systématiquement recherchés, notamment en cas d'infection grave ou récidivante, une antibioprophylaxie ou une vaccination pouvant être proposées chez les sujets à haut risque. PMID:26327976

  9. 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.

  10. 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

  11. 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.

  12. PGNAA of human arthritic synovium for boron neutron capture synovectomy

    SciTech Connect

    Binello, E.; Yanch, J.C.; Shortkroff, S.

    1997-12-01

    Boron neutron capture synovectomy (BNCS), is a proposed new therapy modality for the treatment of rheumatoid arthritis, an autoimmune disease afflicting the joints. The synovium, which is the membrane lining the joint, becomes inflamed and represents the target tissue for therapy. When a joint is unresponsive to drug treatment, physical removal of the synovium, termed synovectomy, becomes necessary. Existing options include surgery and radiation synovectomy. BNCS has advantages over these options in that it is noninvasive and does not require the administration of radioactive substances. Previous studies have shown that the uptake of {sup 10}B by human arthritic synovium ex vivo is high, ranging from 194 to 545 ppm with an unenriched boron compound. While tissue samples remain viable up to 1 week, ex vivo conditions do not accurately reflect those in vivo. This paper presents results from experiments assessing the washout of boron from the tissue and examines the implications for in vivo studies.

  13. An exploratory investigation of causal thinking of arthritics.

    PubMed

    Lowery, B J; Jacobsen, B S; Murphy, B B

    1983-01-01

    Research in academic achievement situations suggests that the causes people give for achievement events are linked to subsequent behaviors, emotions, and expectations. An attributional analysis of the causes arthritics gave for their condition tested the limits of the attributional model in the situation of chronic illness. Results indicated that the assumption that causal thinking occurs needs further testing. Fifteen percent of the subjects did not give causes. Those not giving causes were significantly more anxious, more depressed, and more hostile than those who had constructed causes. In terms of the dimensions of attribution theory, the results suggest that when causes are given, they do not easily fit within the classification scheme currently proposed. Suggestions for testing of the attributional model in clinical situations are offered.

  14. Topical ethosomal capsaicin attenuates edema and nociception in arthritic rats.

    PubMed

    Kumar Sarwa, Khomendra; Rudrapal, Mithun; Mazumder, Bhaskar

    2015-12-01

    In this study, topical ethosomal formulation of capsaicin was prepared and evaluated for bio-efficacy in arthritic rats. Physical and biological characterizations of prepared capsaicin-loaded nano vesicular systems were also carried out. Ethosomal capsaicin showed significant reduction of rat paw edema along with promising antinociceptive action. The topical antiarthritic efficacy of prepared formulation of capsaicin was found more than that of Thermagel, a marketed gel of capsaicin. From toxicological study, no predictable signs of toxicity such as skin irritation (of experimental rats) were observed. Based on this finding, ethosomal capsaicin could be proposed as an effective as well as a safe topical delivery system for the long-term treatment of arthritis and associated inflammo-musculoskeletal disorders. Such exciting result would eventually enlighten the analgesic and anti-inflammatory potential of capsaicin for topical remedy.

  15. Long-term anti-arthritic and anti-osteoporotic effects of raloxifene in established experimental postmenopausal polyarthritis

    PubMed Central

    Jochems, C; Lagerquist, M; Håkansson, C; Ohlsson, C; Carlsten, H

    2008-01-01

    Both oestrogen deficiency and the inflammatory disease contribute to the generalized bone loss seen in postmenopausal rheumatoid arthritis (RA). Oestradiol and the selective oestrogen receptor modulator raloxifene have been shown to ameliorate the disease in collagen-induced arthritis (CIA), a well-established animal model for human RA. The aim of this study was to investigate whether raloxifene-treatment would be beneficial in long-term treatment of established CIA, both regarding anti-arthritic and anti-osteoporotic properties. Female dilute brown agouti mice were ovariectomized and CIA was induced. Raloxifene or vehicle treatment was administered 5 days per week, and the clinical arthritis score was evaluated continuously. At termination, bone mineral density was analysed, paws were collected for histological examination and sera were analysed for markers of bone and cartilage turnover, as well as antibodies to type II collagen and levels of interleukin (IL)-6. Treatment with raloxifene is beneficial in long-term treatment of established CIA. It hampers the disease severity and frequency, protects the joints from destruction and protects against the development of osteoporosis. The proinflammatory cytokine IL-6 was down-regulated in raloxifene-treated mice compared with controls. The serum levels of antibodies to collagen were not affected by raloxifene-treatment. Long-term treatment with raloxifene has both anti-arthritic and anti-osteoporotic effects in established experimental postmenopausal polyarthritis. PMID:18435803

  16. The Pattern of Use of Oral NSAIDs with or without Co-prescription of Gastroprotective Agent for Arthritic Knee by Korean Practitioners

    PubMed Central

    Kim, Hee-Chun; Moon, Young-Wan; Seo, Seung Suk; Lee, Kwang Won; Lee, Ju Hong; Choi, Choong-Hyeok

    2011-01-01

    Purpose The aim of this study was to describe the patterns of use of non-steroidal anti-inflammatory drugs (NSAIDs) for arthritic knees in clinical practice, particularly focusing on the co-prescription of gastroprotective agents for patients with risk factors for adverse gastrointestinal (GI) events. Materials and Methods Each cross-sectional cohort was a group of outpatients visiting 111 physicians who had prescribed NSAIDs for the patients' arthritic knees for more than three consecutive months. A self-administered questionnaire was completed by each patient and physician. Results Nine hundred and forty five patients (48%) of the whole 1,960 patients belonged to the group with a high or very high risk for NSAID-induced gastropathy determined by northern California Health Maintenance Organization guidelines. Overall, only less than half of the patients were given co-prescription of gastroprotective agents, regardless of the presence or absence of GI symptoms and irrespective of the level of risk for NSAID-induced gastropathy. Conclusions The physician prescribing NSAIDs for arthritic knees should monitor any GI symptoms and the patient monitor anylevel for NSAIDinduced gastropathy, and be willing to add gastroprotective agents as necessary in order to prevent serious adverse GI events. PMID:22570835

  17. 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

  18. 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.

  19. 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.

  20. 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.

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

    PubMed Central

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

    2010-01-01

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

  2. 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.

  3. Effect of γ-tocotrienol in counteracting oxidative stress and joint damage in collagen-induced arthritis in rats.

    PubMed

    Radhakrishnan, Ammu; Tudawe, Dulanthi; Chakravarthi, Srikumar; Chiew, Gan Seng; Haleagrahara, Nagaraja

    2014-05-01

    Tocotrienols exhibit a significant anti-inflammatory and antioxidant effect in numerous human diseases. However, the anti-inflammatory and antioxidant effects of tocotrienols in arthritic conditions are not well documented. Therefore, the effect of γ-tocotrienol supplementation against oxidative stress and joint pathology in collagen-induced arthritis in rats was investigated in the present study. Adult female Dark Agouti rats were randomly divided into groups: Control, γ-tocotrienol alone, arthritis alone and arthritis with γ-tocotrienol. Arthritis was induced using 4 mg/kg body weight collagen in complete Freund's adjuvant. The rats were treated orally with 5 mg/kg body weight of γ-tocotrienol between day 21 and day 45. After 45 days, serum C-reactive protein (CRP), tumor necrosis factor (TNF)-α, superoxide dismutase (SOD) and total glutathione (GSH) assays were conducted. γ-tocotrienol significantly reduced the arthritis-induced changes in body weight, CRP, TNF-α, SOD and the total GSH levels. There was a significant reduction in the arthritis-induced histopathological changes in the γ-tocotrienol treatment group. The data indicated that administration of γ-tocotrienol resulted in a significant antioxidant and anti-inflammatory effect on collagen-induced arthritis; therefore, γ-tocotrienol may have therapeutic potential as a long-term anti-arthritic agent in rheumatoid arthritis therapy.

  4. Effect of γ-tocotrienol in counteracting oxidative stress and joint damage in collagen-induced arthritis in rats

    PubMed Central

    RADHAKRISHNAN, AMMU; TUDAWE, DULANTHI; CHAKRAVARTHI, SRIKUMAR; CHIEW, GAN SENG; HALEAGRAHARA, NAGARAJA

    2014-01-01

    Tocotrienols exhibit a significant anti-inflammatory and antioxidant effect in numerous human diseases. However, the anti-inflammatory and antioxidant effects of tocotrienols in arthritic conditions are not well documented. Therefore, the effect of γ-tocotrienol supplementation against oxidative stress and joint pathology in collagen-induced arthritis in rats was investigated in the present study. Adult female Dark Agouti rats were randomly divided into groups: Control, γ-tocotrienol alone, arthritis alone and arthritis with γ-tocotrienol. Arthritis was induced using 4 mg/kg body weight collagen in complete Freund’s adjuvant. The rats were treated orally with 5 mg/kg body weight of γ-tocotrienol between day 21 and day 45. After 45 days, serum C-reactive protein (CRP), tumor necrosis factor (TNF)-α, superoxide dismutase (SOD) and total glutathione (GSH) assays were conducted. γ-tocotrienol significantly reduced the arthritis-induced changes in body weight, CRP, TNF-α, SOD and the total GSH levels. There was a significant reduction in the arthritis-induced histopathological changes in the γ-tocotrienol treatment group. The data indicated that administration of γ-tocotrienol resulted in a significant antioxidant and anti-inflammatory effect on collagen-induced arthritis; therefore, γ-tocotrienol may have therapeutic potential as a long-term anti-arthritic agent in rheumatoid arthritis therapy. PMID:24940448

  5. 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

  6. 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

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

    PubMed

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

    2014-01-01

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

  8. Oligoclonal immunoglobulins and smooth muscle antibodies in arthritic joints.

    PubMed

    Mellbye, O J; Fyrand, O; Brath, H K; Olsen, E

    1980-04-01

    In twelve synovial fluid/serum pairs from patients with various types of seronegative polyarthritis, homogeneous gamma-bands by agarose gel electrophoresis were found in seven of the synovial fluids and in only one of the sera. In six of the fluids with gamma-bands, smooth muscle antibodies (SMA) were also present, usually in a titre identical to that in serum. In fluids with no gamma-bands, no SMA were detected. In forty synovial fluid/serum pairs from paitients with seropositive rheumatoid arthritis, no gamma-bands were detected in the synovial fluids, and SMA were present in only three pairs. Absorption and inhibition experiments did not give evidence that the SMA activity in seronegative polyarthritis was confined to the gamma-bands in the synovial fluids. The SMA activity in the fluids seemed to be directed against both actin and 'non-actin' muscular antigens. The association between locally produced oligoclonal immunoglobulins and possible locally produced SMA with differnet electrophoretic mobility suggests that in some of thes patients there is a local synovial production of oligoclonal antibodies with different specificities. Thus, even if the results may indicate a local virus infection in some arthritic joints, they may also be dur to an unspecific local stimulation of B cells or to a specific antigen stimulation combined with an unspecific co-activation of other antibody-producing cells.

  9. Gastritis in neonatal BALB/cCrSlc mice induced by immunization without adjuvant can be transferred to syngeneic nu/nu recipients.

    PubMed

    Greenwood, D L V; Sentry, J W

    2006-01-01

    The popularly exploited murine neonatal thymectomy experimental autoimmune gastritis (nTx:EAG) model requires the animal to be in a state of lymphopenia. Here we report on a novel murine immunization (without adjuvant) model that can establish a lasting gastritis. We demonstrate that the immunization model (imm:EAG) results in a bona fide autoimmune disease and define the resulting pathology and serology observed and compare it with that reported for human autoimmune gastritis. Immune cells present in the stomachs of imm:EAG gastritic mice include CD8 T cells, CD11b and Gr1 (granulocytes/monocytes) and B cells. We detected circulating antibodies of immunoglobulin G1 (IgG1) subclass, with some IgG(2a) and IgG(2b) reactive to stomach membranes and the parietal cell proton pump. The class and subclass of autoreactive antibodies resulting from imm:EAG suggest a T helper 1 (Th1)/Th2 immune response. We establish that both self-reactive T and B cells from BALB/cCrSlc imm:EAG gastritic mice have the potential to induce a gastritis in BALB/c syngeneic nu/nu recipients. We conclude that this model is likely to be superior to the currently popularly exploited nTx:EAG and provide insight into and an understanding of the mechanisms of and remedies for autoimmunity in an intact immune system.

  10. Quantification of arthritic bone degradation by analysis of 3D micro-computed tomography data

    PubMed Central

    Svensson, Carl-Magnus; Hoffmann, Bianca; Irmler, Ingo M.; Straßburger, Maria; Figge, Marc Thilo; Saluz, Hans Peter

    2017-01-01

    The use of animal models of arthritis is a key component in the evaluation of therapeutic strategies against the human disease rheumatoid arthritis (RA). Here we present quantitative measurements of bone degradation characterised by the cortical bone profile using glucose-6-phosphate isomerase (G6PI) induced arthritis. We applied micro-computed tomography (μCT) during three arthritis experiments and one control experiment to image the metatarsals of the hind paws and to investigate the effect of experimental arthritis on their cortical bone profile. For measurements of the cortical profile we automatically identified slices that are orthogonal to individual metatarsals, thereby making the measurements independent of animal placement in the scanner. We measured the average cortical thickness index (CTI) of the metatarsals, as well as the thickness changes along the metatarsal. In this study we introduced the cortical thickness gradient (CTG) as a new measure and we investigated how arthritis affects this measure. We found that in general both CTI and CTG are able to quantify arthritic progression, whilst CTG was found to be the more sensitive measure. PMID:28290525

  11. Topical dermal application of essential oils attenuates the severity of adjuvant arthritis in Lewis rats

    PubMed Central

    Komeh-Nkrumah, Steva A.; Nanjundaiah, Siddaraju M.; Rajaiah, Rajesh; Yu, Hua; Moudgil, Kamal D.

    2011-01-01

    This study was aimed at examining the effect of an ointment containing essential oils (EO) on the severity of adjuvant arthritis (AA), an experimental model of human rheumatoid arthritis (RA), in Lewis rats and to define the underlying mechanisms. At the onset of AA, rats received topical application twice daily of ointment containing 20% EO or placebo ointment. The synovial fluid (SF) and synovium-infiltrating cells (SIC) of rats were tested for pro-inflammatory cytokines TNF-α and IL-1β. The hind paws and skin were examined histologically. The activity/level of matrix metalloproteinases (MMPs) and anti-mycobacterial heat-shock protein 65 (Bhsp65) antibodies was tested. Arthritic rats treated with ointment containing EO developed less severe clinical arthritis compared to the controls, and this activity was attributable to EO and not the carrier oil. The levels of TNF-α and IL-1β, and the activity of MMPs in SF and SIC-lysate were significantly (p<0.05) reduced in EO-treated arthritic rats compared to the controls. However, the levels of anti-Bhsp65 antibodies were unaffected by treatment. Thus, topical dermal delivery of EO-containing ointment downmodulates the severity of AA in Lewis rats by inhibiting defined mediators of inflammation. Such ointments should be tested in patients with RA and other arthritic conditions. PMID:21544881

  12. Cupressaceae pollen grains modulate dendritic cell response and exhibit IgE-inducing adjuvant activity in vivo.

    PubMed

    Kamijo, Seiji; Takai, Toshiro; Kuhara, Takatoshi; Tokura, Tomoko; Ushio, Hiroko; Ota, Mikiko; Harada, Norihiro; Ogawa, Hideoki; Okumura, Ko

    2009-11-15

    Pollen is considered a source of not only allergens but also immunomodulatory substances, which could play crucial roles in sensitization and/or the exacerbation of allergies. We investigated how allergenic pollens from different plant species (Japanese cedar and Japanese cypress, which belong to the Cupressaceae family, and birch, ragweed, and grass) modulate murine bone marrow-derived dendritic cell (DC) responses and examined the effect of Cupressaceae pollen in vivo using mice. DCs were stimulated with pollen extracts or grains in the presence or absence of LPS. Cell maturation and cytokine production in DCs were analyzed by flow cytometry, ELISA, and/or quantitative PCR. Pollen extracts suppressed LPS-induced IL-12 production and the effect was greatest for birch and grass. Without LPS, pollen grains induced DC maturation and cytokine production without IL-12 secretion and the response, for which TLR 4 was dispensable, was greatest for the Cupressaceae family. Intranasal administration of Cupressaceae pollen in mice induced an elevation of serum IgE levels and airway eosinophil infiltration. Coadministration of ovalbumin with Cupressaceae pollen grains induced ovalbumin-specific IgE responses associated with eosinophil infiltration. The results suggest that modulation of DC responses by pollen differs among the plant families via (1) the promotion of DC maturation and cytokine production by direct contact and/or (2) the inhibition of IL-12 production by soluble factors. The strong DC stimulatory activity in vitro and IgE-inducing activity in mice support the clinical relevance of Cupressaceae pollen to allergies in humans.

  13. Structure of Freund's complete and incomplete adjuvants

    PubMed Central

    Dvorak, Ann M.; Dvorak, H. F.

    1974-01-01

    Emulsions of complete (CFA) and incomplete (IFA) Freund's adjuvants were examined in the light and electron microscopes, and the resulting morphological findings were correlated with the effectiveness of the emulsions as immunological adjuvants. Thick (viscous) emulsions of both IFA and CFA consisted of highly stable, three-dimensional meshworks composed of interconnecting strands of antigen-containing water droplets interspersed in oil phase. Included mycobacteria were confined to this meshwork and were coated with an adherent surface layer of water droplets. Thin Freund's adjuvants were less stable, relatively coarse emulsions, but even in such preparations mycobacteria showed a striking affinity for the surface of water droplets when these contained low concentrations of antigens such as human serum albumin (HSA). The characteristic adjuvant effect of CFA was observed only when associations between mycobacteria and water droplets took place. Thus, no adjuvant effect occurred with oil-in-water (o/w) emulsions, nor when antigen and mycobacteria-in-oil were injected into separate foot pads. Further, a good adjuvant effect was observed even with thin emulsions when mycobacteria-water droplet associations were abundant. These morphological and immunological data suggest that CFA is a device for bringing extrinsic, water-soluble antigens into intimate, stable contact with myco-bacteria, thereby conferring on them the ability to elicit an immunological response qualitatively similar to that induced by mycobacteria-in-oil to the intrinsic antigen, tuberculin. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5 PMID:4605156

  14. Successful immunotherapy with matrix metalloproteinase-derived peptides in adjuvant arthritis depends on the timing of peptide administration

    PubMed Central

    van Bilsen, Jolanda HM; Wagenaar-Hilbers, Josée PA; van der Cammen, Maarten JF; van Dijk, Mariska EA; van Eden, Willem; Wauben, Marca HM

    2002-01-01

    We have recently found that matrix metalloproteinases (MMPs) are targets for T-cell and B-cell reactivity in experimental arthritis. In the present article, we investigate whether modulation of MMP-specific T-cell responses could influence the course of adjuvant arthritis (AA). Lewis rats were treated nasally with MMP peptides prior to or after AA induction. Administration of the MMP-10 or the MMP-16 peptide prior to AA induction reduced the arthritic symptoms. In contrast, administration of the MMP-10 peptide after AA induction aggravated the arthritic symptoms. The present study shows the possible usefulness of MMP peptides for immunotherapy. However, a clear understanding of proper timing of peptide administration is crucial for the development of such therapies. PMID:12106501

  15. Induction of lupus autoantibodies by adjuvants

    USGS Publications Warehouse

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

    2003-01-01

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

  16. Block Copolymers Have Differing Adjuvant Effects on the Primary Immune Response Elicited by Genetic Immunization and on Further Induced Allergy▿

    PubMed Central

    Adel-Patient, Karine; Pothelune, Laetitia; Ah-Leung, Sandrine; Wal, Jean-Michel; Créminon, Christophe; Chatel, Jean-Marc

    2010-01-01

    Block copolymers were recently used to promote gene delivery in various tissues. Using a plasmid encoding a food allergen, bovine β-lactoglobulin (BLG), we studied the effects of block copolymers on gene expression levels and primary immune response and on further induced allergy. Block copolymers (i.e., Tetronic 304, 908, and 1107) and various quantities of DNA were injected into the tibialis muscles of BALB/c mice. The BLG levels in injected muscle and the BLG-specific induced immune response were analyzed after injection. DNA-immunized mice were further experimentally sensitized with BLG, and the effects of block copolymer and DNA doses on allergic sensitization and elicitation were compared. Tetronic 304 induced a 12-fold increase in BLG production, while Tetronic 1107 increased the duration of BLG expression. Different Th1 primary specific immune responses were observed, either strong humoral and cellular (304), only cellular (1107), or weak cellular and humoral (908) responses. After BLG sensitization, increased BLG-specific IgG2a production was observed in all groups of mice independently of the presence and nature of the block copolymer. Increased BLG-specific IgG1 production was also detected after sensitization, except with Tetronic 1107. Compared with naked DNA, Tetronic 304 was the only block polymer that decreased BLG-specific IgE concentrations. However, after allergen challenge, Tetronic 1107 was the only block copolymer to reduce eosinophils and Th2 cytokines in bronchoalveolar lavage (BAL) fluid. Tetronic 304 amplified local inflammation. Each block copolymer elicited a different immune response, although always Th1 specific, in BALB/c mice. PMID:19923567

  17. Block copolymers have differing adjuvant effects on the primary immune response elicited by genetic immunization and on further induced allergy.

    PubMed

    Adel-Patient, Karine; Pothelune, Laetitia; Ah-Leung, Sandrine; Wal, Jean-Michel; Créminon, Christophe; Chatel, Jean-Marc

    2010-01-01

    Block copolymers were recently used to promote gene delivery in various tissues. Using a plasmid encoding a food allergen, bovine beta-lactoglobulin (BLG), we studied the effects of block copolymers on gene expression levels and primary immune response and on further induced allergy. Block copolymers (i.e., Tetronic 304, 908, and 1107) and various quantities of DNA were injected into the tibialis muscles of BALB/c mice. The BLG levels in injected muscle and the BLG-specific induced immune response were analyzed after injection. DNA-immunized mice were further experimentally sensitized with BLG, and the effects of block copolymer and DNA doses on allergic sensitization and elicitation were compared. Tetronic 304 induced a 12-fold increase in BLG production, while Tetronic 1107 increased the duration of BLG expression. Different Th1 primary specific immune responses were observed, either strong humoral and cellular (304), only cellular (1107), or weak cellular and humoral (908) responses. After BLG sensitization, increased BLG-specific IgG2a production was observed in all groups of mice independently of the presence and nature of the block copolymer. Increased BLG-specific IgG1 production was also detected after sensitization, except with Tetronic 1107. Compared with naked DNA, Tetronic 304 was the only block polymer that decreased BLG-specific IgE concentrations. However, after allergen challenge, Tetronic 1107 was the only block copolymer to reduce eosinophils and Th2 cytokines in bronchoalveolar lavage (BAL) fluid. Tetronic 304 amplified local inflammation. Each block copolymer elicited a different immune response, although always Th1 specific, in BALB/c mice.

  18. Devil's Claw (Harpagophytum procumbens): no evidence for anti-inflammatory activity in the treatment of arthritic disease.

    PubMed Central

    Whitehouse, L. W.; Znamirowska, M.; Paul, C. J.

    1983-01-01

    Devil's Claw (Harpagophytum procumbens), an herbal product being marketed in Canada as a home remedy for the relief of arthritic disease, was screened for efficacy with standard preclinical screening methods. At doses 100 times or greater than the recommended daily dose for humans, Devil's Claw was completely ineffective in reducing edema of the rat hind foot induced by either lambda-carrageenan or Mycobacterium butyricum. At concentrations of up to 1 x 10(5) microgram/ml, Devil's Claw was also ineffective as an in-vitro inhibitor of prostaglandin synthetase. These results indicate that Devil's Claw lacks the anti-inflammatory properties possessed by all antiarthritic drugs of the nonsteroidal, anti-inflammatory analgesic type. PMID:6407745

  19. 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

  20. Refractory heparin induced thrombocytopenia with thrombosis (HITT) treated with therapeutic plasma exchange and rituximab as adjuvant therapy.

    PubMed

    Schell, Amy M; Petras, Melissa; Szczepiorkowski, Zbigniew M; Ornstein, Deborah L

    2013-10-01

    We report a case of refractory heparin-induced thrombocytopenia with thrombosis (HITT) with prolonged thrombocytopenia and multiple thrombotic complications that failed to improve despite aggressive treatment. A 60 year old female with a prior history of venous thromboembolism was admitted with an acute pulmonary embolism, and developed HITT after several days on heparin therapy. She suffered multiple complications including bilateral venous limb gangrene, acute renal failure, and refractory thrombocytopenia, leading us to use multimodality therapy including therapeutic plasma exchange (TPE) and rituximab immunosuppression. The patient had transient improvements in her thrombocytopenia with TPE, and rituximab was added in an attempt to reduce antibody production. She eventually required bilateral limb amputation, and only after removal of the gangrenous limbs did her platelet count show sustained improvement. We discuss the possible contribution of infection to her prolonged course.

  1. Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model.

    PubMed

    Quan, Ling-Dong; Yuan, Fang; Liu, Xin-Ming; Huang, Jian-Geng; Alnouti, Yazen; Wang, Dong

    2010-08-02

    N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer has been found to be arthrotropic (joint-targeting) in the adjuvant-induced arthritis (AA) rat model using magnetic resonance imaging (MRI). In this manuscript, we report the quantitative pharmacokinetics and biodistribution (PK/BD) of (125)I-labeled HPMA copolymer-dexamethasone conjugate (P-Dex) in AA rats. Structural parameters of the prodrug such as the molecular weight (MW) and Dex content were found to have strong impact on the PK/BD profiles of P-Dex. The increase of MW (14,000, 24,000, and 42,000 g/mol) and Dex content (0, 151, and 313 micromol/g) enhances the arthrotropism of P-Dex. For the conjugate with highest MW and Dex content (P-H-M(W)/Dex), the percentage of injected doses per gram (ID/g) of ankle synovial tissue at day seventh postadministration is 1% g(-1), which confirms P-Dex as an arthrotropic macromolecular prodrug. For liver and spleen, the ID/g values are 0.51 and 3.64% g(-1), respectively. As an antigen-presenting organ, the sequestration of the prodrug by spleen may be explained by its abnormal enlargement associated with the systemic inflammatory disease model. Gradual reduction of spleen weight due to the inflammation resolution effect of P-Dex may also contribute to the high ID/g values. Increase of Dex content and reduction of MW would increase P-Dex distribution to kidney. The highest ID/g value for kidney at day seventh postadministration (0.91% g(-1)) was found with P-L-M(w) (MW = 14,000 g/mol, Dex content =288 micromol/g), which may suggest kidney tubuli reabsorption of the conjugates. The P-Dex's distribution to heart and lung is minimum.

  2. The absorption enhancement of norisoboldine in the duodenum of adjuvant-induced arthritis rats involves the impairment of P-glycoprotein.

    PubMed

    Duan, Cong; Guo, Jiao-Mei; Dai, Yue; Xia, Yu-Feng

    2017-01-01

    Lindera aggregata (Sims) Kosterm root has been used in traditional Chinese medicine for the treatment of rheumatism palsy, dyspepsia and frequent urination for a long time. Norisoboldine, the main active constituent of this herb drug, possesses outstanding anti-arthritis activity. However, the in vivo disposition of norisoboldine is known to a limited extent, especially under the pathological condition of rheumatoid arthritis (RA). The aim of this study is to investigate whether and how the absorption of norisoboldine is altered in adjuvant-induced arthritis (AIA) rats. Comparative studies of the intestinal absorption of norisoboldine in normal and AIA rats at different pathological stages of the arthritis were performed using in situ single-pass intestinal perfusion, and the effects of an inhibitor of efflux proteins were also investigated. Norisoboldine was shown to be a substrate of P-glycoprotein (P-gp), as P-gp inhibitor verapamil markedly increased the permeability coefficient (Peff ) of norisoboldine by 88% in the intestine of normal rats. Compared with normal rats, AIA rats displayed increased Peff values of norisoboldine by 84% and 86% on day 5 and day 10 after the appearance of the secondary response of arthritis, respectively. Verapamil could eliminate the difference of intestinal absorption of norisoboldine between normal and AIA rats. Further studies showed that impaired expression and activity of P-gp in AIA rats play a decisive role in the absorption enhancement of norisoboldine. Notably, the impairment of P-gp function positively correlated with the severity of arthritis. Copyright © 2016 John Wiley & Sons, Ltd.

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

    PubMed Central

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

    2015-01-01

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

  4. Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA).

    PubMed

    Agmon-Levin, Nancy; Zafrir, Yaron; Kivity, Shaye; Balofsky, Ari; Amital, Howard; Shoenfeld, Yehuda

    2014-12-01

    The objectives of this study were to gather information regarding demographic and clinical characteristics of patients diagnosed with either fibromyalgia (FM) or chronic fatigue (CFS) following hepatitis B vaccination (HBVv) and furthermore to apply the recently suggested criteria of autoimmune (auto-inflammatory) syndromes induced by adjuvants (ASIA), in the aim of identifying common characteristics that may suggest an association between fibromyalgia, chronic fatigue and HBV vaccination. Medical records of 19 patients with CFS and/or fibromyalgia following HBVv immunization were analyzed. All of which were immunized during 1990-2008 in different centers in the USA. All medical records were evaluated for demographics, medical history, the number of vaccine doses, as well as immediate and long term post-immunization adverse events and clinical manifestations. In addition, available blood tests, imaging results, treatments and outcomes were analyzed. ASIA criteria were applied to all patients. The mean age of patients was 28.6 ± 11 years, of which 68.4 % were females. 21.05 % had either personal or familial background of autoimmune disease. The mean latency period from the last dose of HBVv to onset of symptoms was 38.6 ± 79.4 days, ranging from days to a year. Eight (42.1 %) patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neurological manifestations (84.2 %), musculoskeletal (78.9 %), psychiatric (63.1 %), fatigue (63.1 %), gastrointestinal complains (58 %) and mucocutaneous manifestations (36.8 %). Autoantibodies were detected in 71 % of patients tested. All patients fulfilled the ASIA criteria. This study suggests that in some cases CFS and FM can be temporally related to immunization, as part of ASIA syndrome. The appearance of adverse event during immunization, the presence of autoimmune susceptibility and higher titers of autoantibodies all can be suggested as risk

  5. Heart remodeling induced by adjuvant trastuzumab-containing chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2: a prospective study.

    PubMed

    Piotrowski, Grzegorz; Gawor, Rafał; Bourge, Robert C; Stasiak, Arkadiusz; Potemski, Piotr; Gawor, Zenon; Nanda, Navin C; Banach, Maciej

    2013-12-01

    We aimed to investigate the cardiac changes in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with trastuzumab in an adjuvant setting. Two hundred and fifty-three women with HER2-positive breast cancer were included. The assessment of cardiovascular system and echocardiography were performed and compared at baseline, at the termination of trastuzumab therapy and 6 months latter. Left heart remodeling was defined arbitrary as the change in at least one of the analyzed echocardiographic parameters of ≥standard deviation (SD) (in model I) or ≥2×SD (in model II) after 6-month follow-up. After 6-month follow-up 39 (31.7%), 27 (22%), 14 (11.4%), 10 (8.1%), 5 (4.1%) and 1 (0.8%), women had at least one parameter with a change exceeding mean difference ≥SD, respectively; and 30 (24.4%), 9 (7.5%), 3 (2.4%), 2 (1.6%) 1 (0.8%) exceeding mean difference ≥2SD. In stepwise multivariate regression analysis sedentary life style (OR16.7, p=0.003), positive cardiovascular family history (OR 6,9; p=0.013) and left ventricular ejection fraction change after 3 months (OR 1.2; p=0.007) were independent predictors of left heart remodeling in model I, whereas hypertension (OR 5.6; p=0.06) and positive cardiovascular family history (OR 3.9; p=0.032) were independent predictors of heart remodeling in model II. In conclusion, trastuzumab induces LV and left atrial cavity dilatation together with LV systolic function impairment.

  6. An adjuvanted, tetravalent dengue virus purified inactivated vaccine candidate induces long-lasting and protective antibody responses against dengue challenge in rhesus macaques.

    PubMed

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

    2015-04-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-04-29

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

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

    PubMed

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

    2015-12-01

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

  10. Inflammatory responses following intramuscular and subcutaneous immunization with aluminum-adjuvanted or non-adjuvanted vaccines.

    PubMed

    Kashiwagi, Yasuyo; Maeda, Mika; Kawashima, Hisashi; Nakayama, Tetsuo

    2014-06-05

    Aluminum-adjuvanted vaccines are administered through an intramuscular injection (IM) in the US and EU, however, a subcutaneous injection (SC) has been recommended in Japan because of serious muscle contracture previously reported following multiple IMs of antibiotics. Newly introduced adjuvanted vaccines, such as the human papillomavirus (HPV) vaccines, have been recommended through IM. In the present study, currently available vaccines were evaluated through IM in mice. Aluminum-adjuvanted vaccines induced inflammatory nodules at the injection site, which expanded into the intra-muscular space without any muscle degeneration or necrosis, whereas non-adjuvanted vaccines did not. These nodules consisted of polymorph nuclear neutrophils with some eosinophils within the initial 48h, then monocytes/macrophages 1 month later. Inflammatory nodules were observed 6 months after IM, had decreased in size, and were absorbed 12 months after IM, which was earlier than that after SC. Cytokine production was examined in the injected muscular tissues and AS04 adjuvanted HPV induced higher IL-1β, IL-6, KC, MIP-1, and G-CSF levels in muscle tissues than any other vaccine, but similar serum cytokine profiles were observed to those induced by the other vaccines. Currently available vaccines did not induce muscular degeneration or fibrotic scar as observed with muscle contracture caused by multiple IMs of antibiotics in the past.

  11. Nimesulide improves the disease modifying anti-rheumatic profile of methotrexate in mice with collagen-induced arthritis.

    PubMed

    Al-Abd, Ahmed M; Inglis, Julia J; Nofal, Salwa M; Khalifa, Amani E; Williams, Richard O; El-Eraky, Wafaa I; Abdel-Naim, Ashraf B

    2010-10-10

    Methotrexate is a disease modifying anti-rheumatic drug that is widely used for the treatment of rheumatoid arthritis. Nimesulide is a non-steroidal anti-inflammatory drug which is frequently used as adjuvant therapy for symptomatic alleviation of rheumatoid arthritis. In this study, we have evaluated the potential influence of nimesulide on the disease modifying anti-rheumatic properties of methotrexate using the collagen-induced arthritis model. Mice were immunized with collagen type II for the induction of arthritis and treated with methotrexate (2.5mg/kg) twice a week, nimesulide (20mg/kg) every other day or a combination of both drugs. Treatment started one week after the onset of arthritis until day 40. An arthritic index was used to compare the severity of arthritis between different treatments. In addition, articular hyperalgesia, joint stiffness, radiological deterioration and intra-articular leucocytic infiltration were evaluated. Methotrexate alone showed modest but significant analgesic and anti-inflammatory effects, and the effects of nimesulide were comparable. On the other hand, nimesulide significantly improved the disease modifying anti-rheumatic profile of methotrexate in terms of arthritic index and joint mobility. Furthermore, although nimesulide failed to show any radiological evidence of articular protection, it significantly improved methotrexate-induced joint protection as judged by X-ray analysis.

  12. Chemical adjuvants for plasmid DNA vaccines.

    PubMed

    Greenland, John R; Letvin, Norman L

    2007-05-10

    Plasmid DNA vaccines are a promising modality for immunization against a variety of human pathogens. Immunization via multiple routes with plasmid DNA can elicit potent cellular immune responses, and these immunogens can be administered repeatedly without inducing anti-vector immunity. Nonetheless, the immunogenicity of plasmid DNA vaccines has been limited by problems associated with delivery. A number of adjuvants have been designed to improve plasmid DNA immunogenicity, either by directly stimulating the immune system or by enhancing plasmid DNA expression. Chemical adjuvants for enhancing plasmid DNA expression include liposomes, polymers, and microparticles, all of which have shown promise for enhancing the expression and immunogenicity of plasmid DNA vaccines in animal models. Micro- and nanoparticles have not been shown to enhance immune responses to plasmid DNA vaccines. However, formulation of plasmid DNA with some non-particulate polymeric adjuvants has led to a statistically significant enhancement of immune responses. Further development of these technologies will significantly improve the utility of plasmid DNA vaccination.

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

    PubMed

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

    2016-09-14

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

  14. Enhanced gene transfer to arthritic joints using adeno-associated virus type 5: implications for intra-articular gene therapy

    PubMed Central

    Adriaansen, J; Tas, S; Klarenbeek, P; Bakker, A; Apparailly, F; Firestein, G; Jorgensen, C; Vervoordeldonk, M; Tak, P

    2005-01-01

    Background: Gene therapy of the joint has great potential as a new therapeutic approach for the treatment of rheumatoid arthritis (RA). The vector chosen is of crucial importance for clinical success. Objective: To investigate the tropism and transduction efficiency in arthritic joints in vivo, and in synovial cells in vitro, using five different serotypes of recombinant adeno-associated virus (rAAV) encoding ß-galactosidase or green fluorescent protein genes. Methods: rAAV was injected into the ankle joints of rats with adjuvant arthritis after the onset of disease. Synovial tissue was examined at different time points for ß-galactosidase protein and gene expression by in situ staining and polymerase chain reaction (PCR) analysis, respectively. In addition, the ability of rAAV to transduce primary human fibroblast-like synoviocytes from patients with RA was investigated in vitro. Results: Intra-articular injection of the rAAV5 serotype resulted in the highest synovial transduction, followed by much lower expression using rAAV2. Expression of the transgene was already detectable 7 days after injection and lasted for at least 4 weeks. Only background staining was seen for serotypes 1, 3, and 4. Importantly, there was a minimal humoral immune response to rAAV5 compared with rAAV2. Additionally, it was found that both rAAV2 and rAAV5 can efficiently transduce human fibroblast-like synoviocytes obtained from patients with RA. Conclusion: Intra-articular rAAV mediated gene therapy in RA might be improved by using rAAV5 rather than other serotypes. PMID:15878906

  15. Vaccine Adjuvants: from 1920 to 2015 and Beyond

    PubMed Central

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

    2015-01-01

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

  16. 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

  17. 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

  18. Tamarind Seed (Tamarindus indica) Extract Ameliorates Adjuvant-Induced Arthritis via Regulating the Mediators of Cartilage/Bone Degeneration, Inflammation and Oxidative Stress

    PubMed Central

    Sundaram, Mahalingam S.; Hemshekhar, Mahadevappa; Santhosh, Martin S.; Paul, Manoj; Sunitha, Kabburahalli; Thushara, Ram M.; NaveenKumar, Somanathapura K.; Naveen, Shivanna; Devaraja, Sannaningaiah; Rangappa, Kanchugarakoppal S.; Kemparaju, Kempaiah; Girish, Kesturu S.

    2015-01-01

    Medicinal plants are employed in the treatment of human ailments from time immemorial. Several studies have validated the use of medicinal plant products in arthritis treatment. Arthritis is a joint disorder affecting subchondral bone and cartilage. Degradation of cartilage is principally mediated by enzymes like matrix metalloproteinases (MMPs), hyaluronidases (HAase), aggrecanases and exoglycosidases. These enzymes act upon collagen, hyaluronan and aggrecan of cartilage respectively, which would in turn activate bone deteriorating enzymes like cathepsins and tartrate resistant acid phosphatases (TRAP). Besides, the incessant action of reactive oxygen species and the inflammatory mediators is reported to cause further damage by immunological activation. The present study demonstrated the anti-arthritic efficacy of tamarind seed extract (TSE). TSE exhibited cartilage and bone protecting nature by inhibiting the elevated activities of MMPs, HAase, exoglycosidases, cathepsins and TRAP. It also mitigated the augmented levels of inflammatory mediators like interleukin (IL)-1β, tumor necrosis factor-α, IL-6, IL-23 and cyclooxygenase-2. Further, TSE administration alleviated increased levels of ROS and hydroperoxides and sustained the endogenous antioxidant homeostasis by balancing altered levels of endogenous antioxidant markers. Overall, TSE was observed as a potent agent abrogating arthritis-mediated cartilage/bone degradation, inflammation and associated stress in vivo demanding further attention. PMID:26059174

  19. Modern Vaccines/Adjuvants Formulation Session 6: Vaccine &Adjuvant Formulation & Production 15-17 May 2013, Lausanne, Switzerland.

    PubMed

    Fox, Christopher B

    2013-09-01

    The Modern Vaccines/Adjuvants Formulation meeting aims to fill a critical gap in current vaccine development efforts by bringing together formulation scientists and immunologists to emphasize the importance of rational formulation design in order to optimize vaccine and adjuvant bioactivity, safety, and manufacturability. Session 6 on Vaccine and Adjuvant Formulation and Production provided three examples of this theme, with speakers emphasizing the need for extensive physicochemical characterization of adjuvant-antigen interactions, the rational formulation design of a CD8+ T cell-inducing adjuvant based on immunological principles, and the development and production of a rabies vaccine by a developing country manufacturer. Throughout the session, the practical importance of sound formulation and manufacturing design accompanied by analytical characterization was highlighted.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  2. 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.

  3. Mucosal Immunization with Liposome-Nucleic Acid Adjuvants Generates Effective Humoral and Cellular Immunity

    PubMed Central

    Henderson, Angela; Propst, Katie; Kedl, Ross; Dow, Steven

    2012-01-01

    Development of effective new mucosal vaccine adjuvants has become a priority with the increase in emerging viral and bacterial pathogens. We previously reported that cationic liposomes complexed with non-coding plasmid DNA (CLDC) were effective parenteral vaccine adjuvants. However, little is known regarding the ability of liposome-nucleic acid complexes to function as mucosal vaccine adjuvants, or the nature of the mucosal immune responses elicited by mucosal liposome-nucleic acid adjuvants. To address these questions, antibody and T cell responses were assessed in mice following intranasal immunization with CLDC-adjuvanted vaccines. The effects of CLDC adjuvant on antigen uptake, trafficking, and cytokine responses in the airways and draining lymph nodes were also assessed. We found that mucosal immunization with CLDC-adjuvanted vaccines effectively generated potent mucosal IgA antibody responses, as well as systemic IgG responses. Notably, mucosal immunization with CLDC adjuvant was very effective in generating strong and sustained antigen-specific CD8+ T cell responses in the airways of mice. Mucosal administration of CLDC vaccines also induced efficient uptake of antigen by DCs within the mediastinal lymph nodes. Finally, a killed bacterial vaccine adjuvanted with CLDC induced significant protection from lethal pulmonary challenge with Burkholderia pseudomallei. These findings suggest that liposome-nucleic acid adjuvants represent a promising new class of mucosal adjuvants for non-replicating vaccines, with notable efficiency at eliciting both humoral and cellular immune responses following intranasal administration. PMID:21600950

  4. Acute resistance exercise reduces increased gene expression in muscle atrophy of ovariectomised arthritic rats

    PubMed Central

    Furlanetto, Roberto; de Paula Souza, Aletéia; de Oliveira, Anselmo Alves; Nunes, Paulo Ricardo Prado; Michelin, Márcia Antoniazi; Chica, Javier Emilio Lazo; Murta, Eddie Fernando Candido

    2017-01-01

    Objective We studied the effect of resistance exercise (RE) on mRNA levels of atrogin-1, MuRF-1, and myostatin in the gastrocnemius muscle of arthritic rats after loss of ovarian function (LOF). Material and methods Thirty female Wistar rats (nine weeks old, 195.3 ±17.4 grams) were randomly allocated into five groups: control group (CT-Sham; n = 6); group with rheumatoid arthritis (RA; n = 6); group with rheumatoid arthritis subjected to RE (RAEX; n = 6); ovariectomy group with rheumatoid arthritis (RAOV; n = 6); and an ovariectomy group with rheumatoid arthritis subjected to RE (RAOVEX; n = 6). After 15 days of intra-articular injections with Met-BSA the animals were subjected to RE and six hours after workout were euthanised. Results The rheumatoid arthritis provoked reduction in the cross-sectional area (CSA) of muscle fibres, but the CSA was lower in the RAOV when compared to the RA groups. Skeletal muscle atrogin-1 mRNA level was increased in arthritic rats (RA and RAOV), but the atrogin-1 level was higher in RAOV group when compared to other arthritic groups. The Muscle MuRF-1 mRNA level was also increased in the RAOV group. The increased atrogin-1 and MuRF-1 mRNA levels were lower in the RAOVEX group than in the RAOV group. The myostatin mRNA level was similar in all groups, except for the RAOVEX group, in which it was lower than the other groups. Conclusions LOF results in increased loss of skeletal muscle-related ubiquitin ligases (atrogin-1 and MuRF-1). However, the RE reduces the atrogin-1, MuRF-1, and myostatin mRNA levels in muscle of arthritic rats affected by LOF. PMID:28250722

  5. Salicylates in the treatment of arthritic disease. How safe and effective?

    PubMed

    Altman, R D

    1988-11-01

    Despite the adverse effects of aspirin, many physicians still consider it to be the drug of choice for initial treatment of arthritic disorders. Nonsteroidal antiinflammatory drugs (NSAIDs) are better tolerated than aspirin but have similar, although milder, side effects. The nonacetylated salicylates appear to have fewer adverse effects than either aspirin or the NSAIDs and therefore may warrant greater consideration as first-line therapy for arthritis.

  6. Adjuvant-induced joint inflammation causes very rapid transcription of beta-preprotachykinin and alpha-CGRP genes in innervating sensory ganglia.

    PubMed

    Bulling, D G; Kelly, D; Bond, S; McQueen, D S; Seckl, J R

    2001-04-01

    Neuropeptides synthesized in dorsal root ganglia (DRG) have been implicated in neurogenic inflammation and nociception in experimental and clinical inflammatory arthritis. We examined the very early changes in response to adjuvant injection in a rat model of unilateral tibio-tarsal joint inflammation and subsequent monoarthritis. Within 30 min of adjuvant injection ipsilateral swelling and hyperalgesia were apparent, and marked increases in beta-preprotachykinin-A (beta-PPT-A) and alpha-calcitonin gene-related peptide (CGRP)-encoding mRNAs were observed in small-diameter L5 DRG neurones innervating the affected joint. This response was augmented by recruitment of additional small-diameter DRG neurones expressing beta-PPT-A and CGRP transcripts. The increased mRNA was paralleled by initial increases in L5 DRG content of the protein products, substance P and calcitonin gene-related peptide. Within 15 min of adjuvant injection there were increases in electrical activity in sensory nerves innervating a joint. Blockade of this activity prevented the rapid induction in beta-PPT-A and CGRP mRNA expression in DRG neurones. Increased expression of heteronuclear (intron E) beta-PPT-A RNA suggests that increases in beta-PPT-A mRNA levels were, at least in part, due to transcription. Pre-treatment with the protein synthesis inhibitor cycloheximide had no effect upon the early rise in neuropeptide mRNAS: This and the rapid time course of these changes suggest that increased sensory neural discharge and activation of a latent modulator of transcription are involved.

  7. Diatoms and diatomaceous earth as novel poultry vaccine adjuvants.

    PubMed

    Nazmi, A; Hauck, R; Davis, A; Hildebrand, M; Corbeil, L B; Gallardo, R A

    2017-02-01

    Diatoms are single cell eukaryotic microalgae; their surface possesses a porous nanostructured silica cell wall or frustule. Diatomaceous earth (DE) or diatomite is a natural siliceous sediment of diatoms. Since silica has been proved to have adjuvant capabilities, we propose that diatoms and DE may provide an inexpensive and abundant source of adjuvant readily available to use in livestock vaccines.In a first experiment, the safety of diatoms used as an adjuvant for in-ovo vaccination was investigated. In a second experiment, we assessed the humoral immune response after one in-ovo vaccination with inactivated Newcastle Disease Virus (NDV) and DE as adjuvant followed by 2 subcutaneous boosters on d 21 and 29 of age. In both experiments, results were compared to Freund's incomplete adjuvant and aluminum hydroxide.No detrimental effects on hatchability and chick quality were detected after in-ovo inoculation of diatoms and DE in experiments 1 and 2 respectively. In experiment 2 no humoral responses were detected after the in-ovo vaccination until 29 d of age. Seven d after the second subcutaneous booster an antibody response against NDV was detected in chickens that had received vaccines adjuvanted with Freund's incomplete adjuvant, aluminum hydroxide, and DE. These responses became significantly higher 10 d after the second booster. Finally, 15 d after the second booster, the humoral responses induced by the vaccine with Freund's incomplete adjuvant were statistically higher, followed by comparable responses induced by vaccines containing DE or aluminum hydroxide that were significantly higher than DE+PBS, PBS+INDV and PBS alone. From an applied perspective, we can propose that DE can serve as a potential adjuvant for vaccines against poultry diseases.

  8. 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.

  9. 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

  10. Protective immunity induced in Aotus monkeys by a recombinant SERA protein of Plasmodium falciparum: further studies using SERA 1 and MF75.2 adjuvant.

    PubMed Central

    Inselburg, J; Bathurst, I C; Kansopon, J; Barr, P J; Rossan, R

    1993-01-01

    We describe the third of three vaccination trials of Panamanian Aotus monkeys with a recombinant blood-stage antigen derived from the malaria parasite Plasmodium falciparum. Immunization was performed with an N-terminal region of the SERA antigen (serine repeat antigen protein), SERA 1, that contains a 262-amino-acid fragment including amino acids 24 to 285 of the 989-amino-acid SERA protein. Vaccinations were carried out with the recombinant protein mixed with either Freund's, MF75.2, or MF59.2 adjuvant. A control group that did not receive SERA 1 but only MF75.2 adjuvant was included. Monkeys vaccinated with the antigen MF59.2 mixture produced low anti-SERA 1 titers and were not protected. Monkeys vaccinated with antigen and Freund's adjuvant had, in general, a higher average anti-SERA 1 titer (107,278) than did monkeys immunized with SERA 1 and MF75.2 (40, 143), yet monkeys in both groups were well protected. Monkeys that received only MF75.2 developed neither detectable anti-SERA 1 nor anti-P. falciparum antibodies prior to or 10 days after parasite challenge, yet were apparently protected against infection. Monkeys vaccinated with either SERA 1 and Freund's, SERA 1 and MF75.2, or MF75.2 alone and that had been challenged but did not develop a countable parasitemia were treated with a curative dose of mefloquine 100 days after parasite challenge and then rechallenged 40 days later. None of the five rechallenged monkeys that had originally received SERA 1 and Freund's developed a countable parasitemia. Only one of five rechallenged monkeys that originally received SERA 1 and MF75.2 developed a high countable parasitemia, while two animals developed a barely countable parasitemia. Four of the rechallenged monkeys that had originally received only MF75.2 developed a moderate to high countable parasitemia. The results indicate that vaccination with SERA 1 and either Freund's or MF75.2 adjuvant provides protection and vaccination with MF75.2 alone can provide a

  11. DNA Vaccine Electroporation and Molecular Adjuvants

    DTIC Science & Technology

    2016-03-16

    Suschak and Schmaljohn DNA Vaccine Electroporation and Molecular Adjuvants 1 Abstract To date, there is no protective vaccine for Ebola virus...infection. Safety concerns have prevented the use of live-attenuated vaccines , and forced researchers to examine new vaccine formulations. DNA... vaccination is an attractive method for inducing protective immunity to a variety of pathogens, but the low immunogenicity seen in larger animals and

  12. Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies.

    PubMed

    Garcia-Sicilia, José; Arístegui, Javier; Omeñaca, Félix; Carmona, Alfonso; Tejedor, Juan C; Merino, José M; García-Corbeira, Pilar; Walravens, Karl; Bambure, Vinod; Moris, Philippe; Caplanusi, Adrian; Gillard, Paul; Dieussaert, Ilse

    2015-01-01

    In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6-35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3-17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4(+) T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6-35 months and 3-17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.

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

    PubMed Central

    Matos, Marina N.; Cazorla, Silvia I.; Schulze, Kai; Ebensen, Thomas; Guzmán, Carlos A.; Malchiodi, Emilio L.

    2017-01-01

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

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

    PubMed

    Matos, Marina N; Cazorla, Silvia I; Schulze, Kai; Ebensen, Thomas; Guzmán, Carlos A; Malchiodi, Emilio L

    2017-02-01

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

  15. 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

  16. Hepatic toxicity caused by adjuvant CMF/CNF in breast cancer patients and reversal by tamoxifen.

    PubMed

    Hirvikoski, P P; Kumpulainen, E J; Johansson, R T

    1997-07-01

    The purpose of the study was to determine the effect of adjuvant chemotherapy on liver enzymes in breast cancer patients. Furthermore, the effect of tamoxifen on liver enzymes was analyzed. Liver function tests from 194 breast cancer patients who received adjuvant chemotherapy with or without tamoxifen (TAM) were reviewed. Statistically very significant increases were seen in alkaline phosphatase, aspartate acetyl transferase, and gamma glutamyl transferase levels in these patients receiving adjuvant chemotherapy. No statistical changes were noticed in bilirubin levels. If tamoxifen was given together with adjuvant chemotherapy, no changes in liver function tests were detected. Hepatic toxicity was induced in breast cancer patients by adjuvant CMF/CNF therapy (cyclophosphamide, methotrexate, 5-fluorouracil, mitoxantrone). These changes were mostly mild. Adjuvant tamoxifen reduced the increase in liver enzymes caused by adjuvant chemotherapy.

  17. Periaqueductal Grey EP3 Receptors Facilitate Spinal Nociception in Arthritic Secondary Hypersensitivity

    PubMed Central

    Drake, R.A.R.; Leith, J.L.; Almahasneh, F.; Martindale, J.; Wilson, A.W.; Lumb, B.

    2016-01-01

    Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience after tissue injury. Secondary hypersensitivity develops within undamaged tissue adjacent and distant to damaged sites. Spinal neuronal pools innervating regions of secondary hypersensitivity are dominated by descending facilitation that amplifies spinal inputs from unsensitized peripheral nociceptors. Cyclooxygenase–prostaglandin (PG) E2 signaling within the ventrolateral periaqueductal gray (vlPAG) is pronociceptive in naive and acutely inflamed animals, but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown. In naive rats, PG EP3 receptor (EP3R) antagonism in vlPAG modulated noxious withdrawal reflex (EMG) thresholds to preferential C-nociceptor, but not A-nociceptor, activation and raised thermal withdrawal thresholds in awake animals. In rats with inflammatory arthritis, secondary mechanical and thermal hypersensitivity of the hindpaw developed and was associated with spinal sensitization to A-nociceptor inputs alone. In arthritic rats, blockade of vlPAG EP3R raised EMG thresholds to C-nociceptor activation in the area of secondary hypersensitivity to a degree equivalent to that evoked by the same manipulation in naive rats. Importantly, vlPAG EP3R blockade also affected responses to A-nociceptor activation, but only in arthritic animals. We conclude that vlPAG EP3R activity exerts an equivalent facilitation on the spinal processing of C-nociceptor inputs in naive and arthritic animals, but gains in effects on spinal A-nociceptor processing from a region of secondary hypersensitivity. Therefore, the spinal sensitization to A-nociceptor inputs associated with secondary hypersensitivity is likely to be at least partly dependent on descending prostanergic facilitation from the vlPAG. SIGNIFICANCE STATEMENT After tissue damage, sensitivity to painful stimulation develops in undamaged areas (secondary

  18. Adjuvant Treatment of Melanoma

    PubMed Central

    Moreno Nogueira, J. A.; Valero Arbizu, M.; Pérez Temprano, R.

    2013-01-01

    Melanomas represent 4% of all malignant tumors of the skin, yet account for 80% of deaths from skin cancer.While in the early stages patients can be successfully treated with surgical resection, metastatic melanoma prognosis is dismal. Several oncogenes have been identified in melanoma as BRAF, NRAS, c-Kit, and GNA11 GNAQ, each capable of activating MAPK pathway that increases cell proliferation and promotes angiogenesis, although NRAS and c-Kit also activate PI3 kinase pathway, including being more commonly BRAF activated oncogene. The treatment of choice for localised primary cutaneous melanoma is surgery plus lymphadenectomy if regional lymph nodes are involved. The justification for treatment in addition to surgery is based on the poor prognosis for high risk melanomas with a relapse index of 50–80%. Patients included in the high risk group should be assessed for adjuvant treatment with high doses of Interferon-α2b, as it is the only treatment shown to significantly improve disease free and possibly global survival. In the future we will have to analyze all these therapeutic possibilities on specific targets, probably associated with chemotherapy and/or interferon in the adjuvant treatment, if we want to change the natural history of melanomas. PMID:23476798

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

    PubMed

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

    2015-10-01

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

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

    PubMed Central

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

    2008-01-01

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

  1. 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

  2. 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

  3. Treatment Algorithm for Patients with Non-arthritic Hip Pain, Suspect for an Intraarticular Pathology

    PubMed Central

    Jørgensen, R. Wejnold; Dippmann, C.; Dahl, L.; Stürup, J.

    2016-01-01

    Background: The amount of patients referred with longstanding, non-arthritic hip pain is increasing, as are the treatment options. Left untreated hip dysplasia, acetabular retroversion and femoroacetabular impingement (FAI) may lead to osteoarthritis (OA). Finding the right treatment option for the right patient can be challenging in patients with non-arthritic hip pain. Purpose: The purpose of this study was to categorize the radiographic findings seen in patients with longstanding hip pain, suspect for an intraarticular pathology, and provide a treatment algorithm allocating a specific treatment option for each clinical condition. Material and Methods: A review of the literature was performed using Public Medline searches of MeSH terms combined with synonyms for femoroacetabular impingement, acetabular retroversion, periacetabular osteotomy and hip arthroscopy. Results: Radiographic findings associated with acetabular retroversion described in the literature were the crossover sign, the posterior wall sign and the ischial spine sign, while Wiberg’s lateral center-edge angle (CE-angle) together with Leqeusne’s acetabular index indicate hip dysplasia. A Tönnis index >2 indicates osteoarthritis, however unsatisfying results are documented following joint preserving surgery with a Tönnis index >1. Furthermore, ischial spine sign in combination with the posterior wall sign indicates total acetabular retroversion prone to periacetabular osteotomy in contrast to focal retroversion prone to hip arthroscopy. These findings were used creating a treatment algorithm for intraarticular pathologies in patients with longstanding hip pain. Conclusion: Based on the radiographic findings, the algorithm presented in this study can be a helpful tool in the decision-making for the treatment of patients with non-arthritic hip pain, suspect for intraarticular pathologies. PMID:27583059

  4. Femorotibial offset. A morphologic feature of the natural and arthritic knee.

    PubMed

    Eckhoff, D G; Aukerman, R

    1999-11-01

    Eccentric wear identified in retrieval studies of failed total knee arthroplasties may reflect unrecognized intrinsic morphologic characteristics of the knee. This study identifies a previously unreported morphologic offset between the center of the tibia and femur using computed tomography scans in 38 preoperative arthritic knees and 38 controls. There is a statistically significant offset between femur and tibia centers in patients and control subjects. There is no significant difference between patients and control subjects in either AP or mediolateral translation of centers. The clinical relevance of this observation is that it may prompt strategies to address morphologic offset, thereby reducing eccentric wear in total knee arthroplasty.

  5. 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

  6. Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines.

    PubMed

    Savelkoul, Huub F J; Ferro, Valerie A; Strioga, Marius M; Schijns, Virgil E J C

    2015-03-05

    The existence of pathogens that escape recognition by specific vaccines, the need to improve existing vaccines and the increased availability of therapeutic (non-infectious disease) vaccines necessitate the rational development of novel vaccine concepts based on the induction of protective cell-mediated immune responses. For naive T-cell activation, several signals resulting from innate and adaptive interactions need to be integrated, and adjuvants may interfere with some or all of these signals. Adjuvants, for example, are used to promote the immunogenicity of antigens in vaccines, by inducing a pro-inflammatory environment that enables the recruitment and promotion of the infiltration of phagocytic cells, particularly antigen-presenting cells (APC), to the injection site. Adjuvants can enhance antigen presentation, induce cytokine expression, activate APC and modulate more downstream adaptive immune reactions (vaccine delivery systems, facilitating immune Signal 1). In addition, adjuvants can act as immunopotentiators (facilitating Signals 2 and 3) exhibiting immune stimulatory effects during antigen presentation by inducing the expression of co-stimulatory molecules on APC. Together, these signals determine the strength of activation of specific T-cells, thereby also influencing the quality of the downstream T helper cytokine profiles and the differentiation of antigen-specific T helper populations (Signal 3). New adjuvants should also target specific (innate) immune cells in order to facilitate proper activation of downstream adaptive immune responses and homing (Signal 4). It is desirable that these adjuvants should be able to exert such responses in the context of mucosal administered vaccines. This review focuses on the understanding of the potential working mechanisms of the most well-known classes of adjuvants to be used effectively in vaccines.

  7. Learning Impairment in Honey Bees Caused by Agricultural Spray Adjuvants

    PubMed Central

    Ciarlo, Timothy J.; Mullin, Christopher A.; Frazier, James L.; Schmehl, Daniel R.

    2012-01-01

    Background Spray adjuvants are often applied to crops in conjunction with agricultural pesticides in order to boost the efficacy of the active ingredient(s). The adjuvants themselves are largely assumed to be biologically inert and are therefore subject to minimal scrutiny and toxicological testing by regulatory agencies. Honey bees are exposed to a wide array of pesticides as they conduct normal foraging operations, meaning that they are likely exposed to spray adjuvants as well. It was previously unknown whether these agrochemicals have any deleterious effects on honey bee behavior. Methodology/Principal Findings An improved, automated version of the proboscis extension reflex (PER) assay with a high degree of trial-to-trial reproducibility was used to measure the olfactory learning ability of honey bees treated orally with sublethal doses of the most widely used spray adjuvants on almonds in the Central Valley of California. Three different adjuvant classes (nonionic surfactants, crop oil concentrates, and organosilicone surfactants) were investigated in this study. Learning was impaired after ingestion of 20 µg organosilicone surfactant, indicating harmful effects on honey bees caused by agrochemicals previously believed to be innocuous. Organosilicones were more active than the nonionic adjuvants, while the crop oil concentrates were inactive. Ingestion was required for the tested adjuvant to have an effect on learning, as exposure via antennal contact only induced no level of impairment. Conclusions/Significance A decrease in percent conditioned response after ingestion of organosilicone surfactants has been demonstrated here for the first time. Olfactory learning is important for foraging honey bees because it allows them to exploit the most productive floral resources in an area at any given time. Impairment of this learning ability may have serious implications for foraging efficiency at the colony level, as well as potentially many social interactions

  8. Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies

    PubMed Central

    Garcia-Sicilia, José; Arístegui, Javier; Omeñaca, Félix; Carmona, Alfonso; Tejedor, Juan C; Merino, José M; García-Corbeira, Pilar; Walravens, Karl; Bambure, Vinod; Moris, Philippe; Caplanusi, Adrian; Gillard, Paul; Dieussaert, Ilse

    2015-01-01

    In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6–35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3–17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4+ T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6–35 months and 3–17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158. PMID:26176592

  9. Innate immunity and adjuvants

    PubMed Central

    Akira, Shizuo

    2011-01-01

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  10. 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

  11. How to define green adjuvants.

    PubMed

    Beck, Bert; Steurbaut, Walter; Spanoghe, Pieter

    2012-08-01

    The concept 'green adjuvants' is difficult to define. This paper formulates an answer based on two approaches. Starting from the Organisation for Economic Cooperation and Development (OECD) definition for green chemistry, production-based and environmental-impact-based definitions for green adjuvants are proposed. According to the production-based approach, adjuvants are defined as green if they are manufactured using renewable raw materials as much as possible while making efficient use of energy, preferably renewable energy. According to the environmental impact approach, adjuvants are defined as green (1) if they have a low human and environmental impact, (2) if they do not increase active ingredient environmental mobility and/or toxicity to humans and non-target organisms, (3) if they do not increase the exposure to these active substances and (4) if they lower the impact of formulated pesticides by enhancing the performance of active ingredients, thus potentially lowering the required dosage of active ingredients. Based on both approaches, a tentative definition for 'green adjuvants' is given, and future research and legislation directions are set out.

  12. Classification of Laser Vaccine Adjuvants

    PubMed Central

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

    2016-01-01

    An immunologic adjuvant, which enhances the magnitude and quality of immune responses to vaccine antigens, has become an essential part of modern vaccine practice. Chemicals and biologicals have been typically used for this purpose, but there are an increasing number of studies that are being conducted on the vaccine adjuvant effect of laser light on the skin. Currently, four different types or classes of laser devices have been shown to systemically enhance immune responses to intradermal vaccination: ultra-short pulsed lasers, non-pulsed lasers, non-ablative fractional lasers and ablative fractional lasers. Aside from involving the application of laser light to the skin in a manner that minimizes discomfort and damage, each type of laser vaccine adjuvant involves emission parameters, modes of action and immunologic adjuvant effects that are quite distinct from each other. This review provides a summary of the four major classes of “laser vaccine adjuvant” and clarifies and resolves their characteristics as immunologic adjuvants. These aspects of each adjuvant’s properties will ultimately help define which laser would be most efficacious in delivering a specific clinical benefit with a specific vaccine. PMID:27104047

  13. CpG oligodeoxynucleotides as mucosal adjuvants

    PubMed Central

    Iho, Sumiko; Maeyama, Jun-ichi; Suzuki, Fumiko

    2015-01-01

    Bacterial DNA comprising palindromic sequences and containing unmethylated CpG is recognized by toll-like receptor 9 of plasmacytoid dendritic cells (pDCs) and induces the production of interferon-α and chemokines, leading to the activation of a Th1 immune response. Therefore, synthetic equivalents of bacterial DNA (CpG oligodeoxynucleotides) have been developed for clinical applications. They are usually phosphorothioated for in vivo use; this approach also leads to adverse effects as reported in mouse models.Mucosal vaccines that induce both mucosal and systemic immunity received substantial attention in recent years. For their development, phosphodiester-linked oligodeoxynucleotides, including the sequence of a palindromic CpG DNA may be advantageous as adjuvants because their target pDCs are present right there, in the mucosa of the vaccination site. In addition, the probability of adverse effects is believed to be low. Here, we review the discovery of such CpG oligodeoxynucleotides and their possible use as mucosal adjuvants. PMID:25751765

  14. The ultrastructure of tomatine adjuvant.

    PubMed

    Yang, Ya-Wun; Sheikh, Nadeem A; Morrow, W J W

    2002-12-01

    The tomatine adjuvant, consisting of tomatine, n-octyl-beta-D-glucopyranoside, phosphatidylethanolamine, cholesterol, and ovalbumin, has recently been shown to potentiate the immunogenicity of protein antigen and elicit cytotoxic T-lymphocyte responses in immunized animals. The physicochemical properties of tomatine adjuvant have not been characterized. The aim of this study was to examine the microstructure of this complex formulation, as directly related to its physicochemical properties. To elucidate the micromorphology of this system, the tomatine adjuvant was separated by isopycnic ultracentrifugation, followed by freeze fracturing and examination by transmission and scanning electron microscopy. The adjuvant mixture was shown to be composed of several micro- and nano-structures. The major fraction obtained from isopycnic separation was shown to consist of flaky needle-like microcrystals, approximately 80-160 nm in width and 2-4 microm in length. The tomatine crystals alone in 0.9% NaCl, on the other hand, were shown to be elongated hollow tubular crystals of hundreds of nanometers up to a few microns in length, along which n-octyl-beta-glucopyranoside was speculated to serve as a seeding microtemplate for gel crystallization of protein complexes. Indented marks within the gel phase were observed in the freeze fractured replicas of the adjuvant, suggesting that protein complexes may have been crystallized or precipitated within the gels. Several other forms of micro- and nano-structures were also observed, showing multiple-dispersion features with gel characteristics. The presence of gel crystalline and multiple-dispersed phases is postulated to contribute to the sustained immunopotentiation effect of tomatine adjuvant.

  15. Using gait analysis to assess weight bearing in rats with Freund׳s complete adjuvant-induced monoarthritis to improve predictivity: Interfering with the cyclooxygenase and nerve growth factor pathways.

    PubMed

    Ängeby Möller, Kristina; Berge, Odd-Geir; Finn, Anja; Stenfors, Carina; Svensson, Camilla I

    2015-06-05

    Lack of predictive power for drug effects has been a major criticism against animal pain models. It is therefore important to define the utility and limitations of different models. The aim of this study was to extend previous work on gait analysis as a tool to investigate pharmacological effects in monoarthritic rats, specifically to test the hypothesis that monoarthritis induced by Freund׳s complete adjuvant (FCA) provides a better estimate of overall analgesic efficacy of established, and novel, clinically effective and ineffective therapeutic approaches. Male rats injected intra-articularly into one ankle joint with FCA (1.0mg/ml) were treated with the monoclonal antibody to nerve growth factor (NGF), MEDI-578, the inhibitors of tropomyosin receptor kinases A, B and C (pan-Trk) AZ6623 or AZ7092, the transient receptor potential vanilloid 1 (TRPV1) inhibitor AZD1386, or the cyclooxygenase (COX) inhibitors naproxen, ibuprofen, valdecoxib or rofecoxib. Effects on weight bearing during locomotion were tested using video capture of print images. The apparent efficacy in this model was Trk inhibitors≥anti-NGF antibody>COX inhibitors. The TRPV1 inhibitor was ineffective. Together with previous data, the results support using gait-related parameters in the monoarthritis model. FCA as induction agent seems to provide a good overall prediction of analgesic efficacy in disorders with inflammatory joint pain.

  16. Can an anterior quadriceps release improve range of motion in the stiff arthritic knee?

    PubMed

    Tarabichi, Samih; Tarabichi, Yasir

    2010-06-01

    We hypothesize that tethering adhesions of the quadriceps muscle are the major pathological structures responsible for a limited range of motion in the stiff arthritic knee. Forty-two modified quadriceps muscle releases were performed on 24 patients with advanced osteoarthritis scheduled for total knee arthroplasty. The ranges of motion were documented intraoperatively both before and immediately after the release. Passive flexion improved significantly in all patients (mean, 32.4 degrees of improvement, P < .001) following a modified quadriceps release, despite any presence of osteophytes or severe deformities. These results strongly implicate adhesions of the quadriceps muscle to the underlying femur, which prevent the distal excursion of the quadriceps tendon, as the restrictive pathology preventing deep flexion in patients with osteoarthritis.

  17. Adjuvant therapy in pancreatic cancer.

    PubMed

    Jones, Owain Peris; Melling, James Daniel; Ghaneh, Paula

    2014-10-28

    Pancreatic cancer remains one of the leading causes of cancer related death worldwide with an overall five-year survival of less than 5%. Potentially curative surgery, which alone can improve 5-year survival to 10%, is an option for only 10%-20% of patients at presentation owing to local invasion of the tumour or metastatic disease. Adjuvant chemotherapy has been shown to improve 5-year survival to 20%-25% but conflicting evidence remains with regards to chemoradiation. In this article we review the current evidence available from published randomised trials and discuss ongoing phase III trials in relation to adjuvant therapy in pancreatic cancer.

  18. Phenotypic characterization of type II collagen-induced arthritis in Wistar rats.

    PubMed

    Song, Hou-Pan; Li, Xin; Yu, Rong; Zeng, Guang; Yuan, Zhen-Yi; Wang, Wei; Huang, Hui-Yong; Cai, Xiong

    2015-10-01

    The aim of the present study was to determine a more specific, efficient and simple method for the induction of collagen-induced arthritis (CIA) in rats. Different strains of rats were injected at the base of the tail with bovine type II collagen (CII) emulsified in incomplete Freund's adjuvant (IFA). The onset and severity of arthritis were evaluated by clinical assessment. The established CIA model was analyzed using a comprehensive examination of clinical, hematological, histological and radiological parameters. The results demonstrated that Wistar rats were the most susceptible strain to CIA followed by Wistar Furth rats, with Sprague Dawley rats being the least susceptible. Following primary and booster immunization, female Wistar rats developed severe arthritis, with an incidence of >83% and low variability in clinical signs. The development of arthritis was accompanied by a significantly elevated erythrocyte sedimentation rate compared with that in the control rats. The radiographic examination revealed bone matrix resorption, considerable soft tissue swelling, periosteal new bone formation and bone erosion in the arthritic joints of the CIA rats. Histopathologically, the synovial joints of CIA rats were characterized by synovial hyperplasia, pannus formation, marked cellular infiltration, bone and cartilage erosion and narrowing of the joint space. The administration of an intradermal injection of only 200 µg bovine CII emulsified in IFA at the base of the tail therefore leads to the successful development of a CIA rat model. This well-characterized CIA rat model could be specifically used to study the pathophysiology of human rheumatoid arthritis as well as to test and develop anti-arthritic agents for humans.

  19. QS-21: a potent vaccine adjuvant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    QS-21 is an potent adjuvant derived from the bark of a Chilean tree, Quillaja saponaria. One of the advantages of this adjuvant is that it promotes a balanced humoral and cell-mediaed immune response and can be widely applicable to a variety of vaccines. This adjuvant has used for some veterinary va...

  20. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Five new drift control adjuvants were sele...

  1. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Four new drift control adjuvants were sele...

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

    PubMed Central

    Kitayama, Shuichi; Zhang, Rong; Liu, Tian-Yi; Ueda, Norihiro; Iriguchi, Shoichi; Yasui, Yutaka; Kawai, Yohei; Tatsumi, Minako; Hirai, Norihito; Mizoro, Yasutaka; Iwama, Tatsuaki; Watanabe, Akira; Nakanishi, Mahito; Kuzushima, Kiyotaka; Uemura, Yasushi; Kaneko, Shin

    2016-01-01

    Summary Vα24 invariant natural killer T (iNKT) cells are a subset of T lymphocytes implicated in the regulation of broad immune responses. They recognize lipid antigens presented by CD1d on antigen-presenting cells and induce both innate and adaptive immune responses, which enhance effective immunity against cancer. Conversely, reduced iNKT cell numbers and function have been observed in many patients with cancer. To recover these numbers, we reprogrammed human iNKT cells to pluripotency and then re-differentiated them into regenerated iNKT cells in vitro through an IL-7/IL-15-based optimized cytokine combination. The re-differentiated iNKT cells showed proliferation and IFN-γ production in response to α-galactosylceramide, induced dendritic cell maturation and downstream activation of both cytotoxic T lymphocytes and NK cells, and exhibited NKG2D- and DNAM-1-mediated NK cell-like cytotoxicity against cancer cell lines. The immunological features of re-differentiated iNKT cells and their unlimited availability from induced pluripotent stem cells offer a potentially effective immunotherapy against cancer. PMID:26862702

  3. 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

  4. Adjuvant Cationic Liposomes Presenting MPL and IL-12 Induce Cell Death, Suppress Tumor Growth, and Alter the Cellular Phenotype of Tumors in a Murine Model of Breast Cancer

    PubMed Central

    2015-01-01

    Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1β and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1β, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80+ macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of Ki-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response. PMID:25179345

  5. Key roles of adjuvants in modern vaccines.

    PubMed

    Reed, Steven G; Orr, Mark T; Fox, Christopher B

    2013-12-01

    Vaccines containing novel adjuvant formulations are increasingly reaching advanced development and licensing stages, providing new tools to fill previously unmet clinical needs. However, many adjuvants fail during product development owing to factors such as manufacturability, stability, lack of effectiveness, unacceptable levels of tolerability or safety concerns. This Review outlines the potential benefits of adjuvants in current and future vaccines and describes the importance of formulation and mechanisms of action of adjuvants. Moreover, we emphasize safety considerations and other crucial aspects in the clinical development of effective adjuvants that will help facilitate effective next-generation vaccines against devastating infectious diseases.

  6. Environmental impact of adjuvants in crop protection.

    PubMed

    Ryckaert, B; Spanoghe, P; Steurbaut, W; Heremans, B; Haesaert, G; de Coen, W

    2005-01-01

    The overall performance of chemical and biological plant protection products is enhanced by the use of adjuvants in the formulation (formulation adjuvants) or in the spray tank (spray adjuvants). Both types of adjuvants aim to stabilize the formulation, to improve the efficiency of the active ingredients and to reduce application and environmental risks. As an important part of the formulation, both quantitatively and qualitatively, the environmental impact and toxicology of adjuvants can not always be considered as inert. However, little is known of their impact as part of plant protection products compared with the active substances. Therefore an experimental framework is needed as a tool for a consistent environmental legislation.

  7. 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.

  8. Role of toll-like receptors and their adaptors in adjuvant immunotherapy for cancer.

    PubMed

    Seya, Tsukasa; Akazawa, Takashi; Uehori, Junji; Matsumoto, Misako; Azuma, Ichiro; Toyoshima, Kumao

    2003-01-01

    The potentiation of immune responses to tumor-associated antigen (Ag) is a pivotal issue in immunotherapy for cancer and thus requires the use of adjuvants, which are involved in efficient antibody (Ab) production and killer cell induction. The efficacy for tumor regression of a number of adjuvants that have been applied to immunotherapy in humans and tumor-bearing animal models has been tested without understanding of the function of adjuvants. Recent findings on the function of Toll-like receptors (TLRs) and their adaptors facilitated the elucidation of the molecular basis of adjuvant activity. TLR signaling was found to induce interferons (IFNs), chemokines and proinflammatory cytokines and mature dendritic cells (DCs) for enhanced efficiency in antigen presentation. The mediators then play a crucial role in the organization of acquired immunity and, together with matured DCs, activate cytotoxic T cells (CTL) and NK cells. These TLR outputs vary among adjuvants, which may depend on adjuvant-specific selection of appropriate sets of TLRs and their adaptors. Here we review how a variety of host immune responses are induced by an individual adjuvant to confer an adjuvant-specific anti-tumor immunity. We elaborate specifically on two adjuvants, BCG-cell wall skeleton and double-stranded RNA (dsRNA). The former activates TLR2/4 on DCs and induces tumor-specific CTL allowing general application to patients with surgically dissected cancer and improving prognosis, while the latter activates TLR3 on DCs to release type 1 IFN that induces tumor cell apoptosis and NK-mediated tumor cytotoxicity.

  9. Antibody response in silver catfish (Rhamdia quelen) immunized with a model antigen associated with different adjuvants

    PubMed Central

    Pavan, T.R.; Di Domenico, J.; Kirsten, K.S.; Nied, C.O.; Frandoloso, R.; Kreutz, L.C.

    2016-01-01

    Adjuvants are essential to boost the immune response to inoculated antigen and play a central role in vaccine development. In this study, we investigated the efficacy of several adjuvants in the production of anti-bovine serum albumin (BSA) antibodies in silver catfish. Two hundred and seventy juvenile silver catfish (60–80 g) of both sexes were intraperitoneally vaccinated with BSA (200 µg/fish) alone or mixed to the following adjuvants: Freund’s complete adjuvant (FCA), Freund’s incomplete adjuvant (FIA), aluminum hydroxide (AlOH), Montanide, four types of cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs) and three concentrations of β-glucan, and the immune enhancing property was evaluated by measuring anti-BSA antibodies in blood samples at biweekly intervals. Our results demonstrated that CpGs ODNs and β-glucan were as effective as classical adjuvants (FCA, FIA, AlOH and Montanide) in promoting anti-BSA antibodies and that the kinetics of antibody production induced by all adjuvants used in our study had a similar trend to that observed in other fish species, with a peak at 28 days post-vaccination. These results may be useful for the selection of adjuvants for vaccine formulation intended for silver catfish and for the development of vaccine and vaccination strategies to other fish species. PMID:27464022

  10. Adjuvants and myeloid-derived suppressor cells: enemies or allies in therapeutic cancer vaccination.

    PubMed

    Fernández, Audry; Oliver, Liliana; Alvarez, Rydell; Fernández, Luis E; Lee, Kelvin P; Mesa, Circe

    2014-01-01

    Adjuvants are a critical but largely overlooked and poorly understood component included in vaccine formulations to stimulate and modulate the desired immune responses to an antigen. However, unlike in the protective infectious disease vaccines, adjuvants for cancer vaccines also need to overcome the effect of tumor-induced suppressive immune populations circulating in tumor-bearing individuals. Myeloid-derived suppressor cells (MDSC) are considered to be one of the key immunosuppressive populations that inhibit tumor-specific T cell responses in cancer patients. This review focuses on the different signals for the activation of the immune system induced by adjuvants, and the close relationship to the mechanisms of recruitment and activation of MDSC. This work explores the possibility that a cancer vaccine adjuvant may either strengthen or weaken the effect of tumor-induced MDSC, and the crucial need to address this in present and future cancer vaccines.

  11. Mucosal SIV Vaccines Comprising Inactivated Virus Particles and Bacterial Adjuvants Induce CD8+ T-Regulatory Cells that Suppress SIV-Positive CD4+ T-Cell Activation and Prevent SIV Infection in the Macaque Model

    PubMed Central

    Andrieu, Jean-Marie; Chen, Song; Lai, Chunhui; Guo, Weizhong; Lu, Wei

    2014-01-01

    A new paradigm of mucosal vaccination against human immunodeficiency virus (HIV) infection has been investigated in the macaque model. A vaccine consisting of inactivated simian immunodeficiency virus (SIV)mac239 particles together with a living bacterial adjuvant (either the Calmette and Guerin bacillus, Lactobacillus plantarum or Lactobacillus rhamnosus) was administered to macaques via the vaginal or oral/intragastric route. In contrast to all established human and veterinary vaccines, these three vaccine regimens did not elicit SIV-specific antibodies nor cytotoxic T-lymphocytes but induced a previously unrecognized population of non-cytolytic MHCIb/E-restricted CD8+ T-regulatory cells that suppressed the activation of SIV-positive CD4+ T-lymphocytes. SIV reverse transcription was thereby blocked in inactivated CD4+ T-cells; the initial burst of virus replication was prevented and the vaccinated macaques were protected from a challenge infection. For 3–14 months after intragastric immunization, 24 macaques were challenged intrarectally with a high dose of SIVmac239 or with the heterologous strain SIV B670 (both strains grown on macaques PBMC). Twenty-three of these animals were found to be protected for up to 48 months while all 24 control macaques became infected. This protective effect against SIV challenge together with the concomitant identification of a robust ex vivo correlate of protection suggests a new approach for developing an HIV vaccine in humans. The induction of this new class of CD8+ T-regulatory cells could also possibly be used therapeutically for suppressing HIV replication in infected patients and this novel tolerogenic vaccine paradigm may have potential applications for treating a wide range of immune disorders and is likely to may have profound implications across immunology generally. PMID:25071760

  12. Use of a whole-slide imaging system to assess the presence and alteration of lymphatic vessels in joint sections of arthritic mice.

    PubMed

    Shi, J X; Liang, Q Q; Wang, Y J; Mooney, R A; Boyce, B F; Xing, L

    2013-11-01

    We investigated the presence and alteration of lymphatic vessels in joints of arthritic mice using a whole-slide imaging system. Joints and long bone sections were cut from paraffin blocks of two mouse models of arthritis: meniscal-ligamentous injury (MLI)-induced osteoarthritis (OA) and TNF transgene (TNF-Tg)-induced rheumatoid arthritis (RA). MLI-OA mice were fed a high fat diet to accelerate OA development. TNF-Tg mice were treated with lymphatic growth factor VEGF-C virus to stimulate lymphangiogenesis. Sections were double immunofluorescence stained with anti-podoplanin and alpha-smooth muscle actin antibodies. The area and number of lymphatic capillaries and mature lymphatic vessels were determined using a whole-slide imaging system and its associated software. Lymphatic vessels in joints were distributed in soft tissues mainly around the joint capsule, ligaments, fat pads and muscles. In long bones, enriched lymphatic vessels were present in the periosteal areas adjacent to the blood vessels. Occasionally, lymphatic vessels were observed in the cortical bone. Increased lymphatic capillaries, but decreased mature lymphatic vessels, were detected in both OA and RA joints. VEGF-C treatment increased lymphatic capillary and mature vessel formation in RA joints. Our findings suggest that the lymphatic system may play an important role in arthritis pathogenesis and treatment.

  13. Drug targeting to arthritic region via folic acid appended surface-engineered multi-walled carbon nanotubes.

    PubMed

    Kayat, Jitendra; Mehra, Neelesh Kumar; Gajbhiye, Virendra; Jain, Narendra Kumar

    2016-01-01

    This study was aimed at developing and investigating folate anchored carbon nanotubes for targeting an anti-arthritic drug, Methotrexate (MTX) to inflammatory arthritic region. The folic acid (FA) was conjugated to amidated multi-walled carbon nanotubes (MWCNTs) and confirmed by Fourier transform infrared (FTIR), (1)H NMR spectroscopy and X-ray diffraction analysis. The MTX was loaded into the pristine and functionalized-MWCNTs and extensively characterized in vitro and in vivo studies. The drug entrapment efficiency was found high in folate conjugated MWCNTs. In vitro drug release in PBS (pH 7.4) from pristine MWCNTs and folate conjugated MWCNTs formulation was found to be 66.35 ± 2.3 and 56.88 ± 1.9% in 24 h, respectively. Folate conjugated MWCNTs significantly increased (p < 0.005) the percentage inhibition of arthritis, biological half-life and volume of distribution of MTX as compared to MTX-loaded naked MWCNTs as well as free MTX. In in vivo biodistribution studies, MTX was found to be significantly higher (p < 0.005) in arthritic joints from folate functionalized MWCNTs as compared to free drug as well as drug-loaded naked MWCNTs. The present outcomes highlights the propensity of drug-loaded functionalized MWCNTs to alter the pharmacokinetics as well as sustained and targeted drug delivery system as well.

  14. Biosafe Nanoscale Pharmaceutical Adjuvant Materials

    PubMed Central

    Jin, Shubin; Li, Shengliang; Wang, Chongxi; Liu, Juan; Yang, Xiaolong; Wang, Paul C.; Zhang, Xin; Liang, Xing-Jie

    2014-01-01

    Thanks to developments in the field of nanotechnology over the past decades, more and more biosafe nanoscale materials have become available for use as pharmaceutical adjuvants in medical research. Nanomaterials possess unique properties which could be employed to develop drug carriers with longer circulation time, higher loading capacity, better stability in physiological conditions, controlled drug release, and targeted drug delivery. In this review article, we will review recent progress in the application of representative organic, inorganic and hybrid biosafe nanoscale materials in pharmaceutical research, especially focusing on nanomaterial-based novel drug delivery systems. In addition, we briefly discuss the advantages and notable functions that make these nanomaterials suitable for the design of new medicines; the biosafety of each material discussed in this article is also highlighted to provide a comprehensive understanding of their adjuvant attributes. PMID:25429253

  15. Effect of Different Doses of Dexmedetomidine as Adjuvant in Bupivacaine -Induced Subarachnoid Block for Traumatized Lower Limb Orthopaedic Surgery: A Prospective, Double-Blinded and Randomized Controlled Study

    PubMed Central

    Halder, Susanta; Mandal, Debabrata; Chandra, Mainak; Ray, Souradeep; Biswas, Madhuri Ranjana; Mandal, Parthojit; Das, Tanuka

    2014-01-01

    Background and Aims: Improved pain management for blunt trauma to the lower extremity has shown to reduce morbidity, induce early ambulation and improve long-term outcomes. Dexmedetomidine; a selective α-2 agonist; has recently been used intrathecally in different doses to prolong spinal anaesthesia. We evaluated the effect of adding two different doses of dexmedetomidine to hyperbaric bupivacaine for spinal anaesthesia. The primary endpoints were the onset and duration of sensory, motor block and duration of analgesia. Materials and Methods: Eighty patients, (20-60yrs) posted for elective lower limb orthopedic surgery of traumatic origin under spinal anaesthesia were divided into 2 equal groups (Group D5&D10) in a randomized, double-blind fashion. In this prospective parallel group study, group D5(n=40) 3ml 0.5% hyperbaric bupivacaine+5μg dexmedetomidine in 0.5 ml of normal saline and group D10 (n=40) 3ml 0.5% bupivacaine+10μg dexmedetomidine in 0.5 ml of normal saline were administered intrathecally. Sensory and motor block onset times and block durations, time to first analgesic use, total analgesic need, postoperative VAS, hemodynamics and side effects were recorded for each patient. Results: Though with similar demographic profile in both groups, sensory and motor block in group D10(p<0.05) was earlier than group D5. Sensory, motor block duration and time to first analgesic use were significantly longer and the need for rescue analgesics was lower in group D10(p<0.05) than D5. 24 h VAS score was significantly lower in group D10(p<0.05). Intergroup hemodynamics was comparable (p>0.05) without any appreciable side effects. Conclusion: Spinal dexmedetomidine increases the sensory, motor block duration and time to first analgesic use, and decreases analgesic consumption in a dose-dependent manner PMID:25584237

  16. The effect of adjuvant immunotherapy on tumor recurrence after segmental resection of carcinogen-induced Wistar/Furth primary bowel adenocarcinomas

    SciTech Connect

    Steele, G. Jr.; Harte, P.J.; Rayner, A.A.; Corson, J.M.; Madara, J.; Munroe, A.E.; King, V.P.; Wilson, R.E.

    1982-01-01

    Primary bowel tumors were induced in Wistar/Furth (W/Fu) rats by 16 weekly subcutaneous injections of 1,2-Dimethylhydrazine (DMH). After ''curative'' resection of primary adenocarcinomas of the colon, 75% of control rats who received no further treatment developed local or regional recurrence within 22 wk. In 4 separate experiments, rats immunized after primary tumor resection by 3 weekly subcutaneous inoculations of 1 x 10/sup 6/ irradiated (10,000 rad) DMH-W15 sarcoma cells (no tumor-associated antigens cross-reacting with bowel adenocarcinomas) developed recurrent tumor at a rate similar to the controls. By contrast, after primary bowel tumor resection, rats immunized with DMH-W-163 colon adenocarcinoma (possessing tumor-associated antigens cross-reactive with W/Fu bowel adenocarcinomas) showed a consistently reduced rate of local or regional recurrence compared to either of the controls (x/sup 2/ = 4.62, p < 0.05) or the rats immunized with sarcomas (X/sup 2/ = 5.42, p < 0.05)= 4.62, p < 0.05). By 22 wk after primary tumor resection, only 35% of the DMH-W-163-immunized animals in each of the 4 experiments showed recurrence. No deaths from recurrences were note in any of the experimental groups after this time, and selected animals sacrificed in the immunized groups up to 30 wk after primary tumor resection were documented to be disease-free. Protection against tumor recurrence was, therefore, a reflection of increased disease-free survival. No change in the effectiveness of immunoprotection in this model could be demonstrated after resection of less invasive primary tumors. These data reflect the utility of a new model in which modification of the natural history of individual primary bowel adenocarcinomas can be examined. The similarities and differences between this system and humans with colon cancer are discussed.

  17. Salidroside ameliorates arthritis-induced brain cognition deficits by regulating Rho/ROCK/NF-κB pathway.

    PubMed

    Zhu, Lingpeng; Chen, Tong; Chang, Xiayun; Zhou, Rui; Luo, Fen; Liu, Jingyan; Zhang, Kai; Wang, Yue; Yang, Ying; Long, Hongyan; Liu, Yu; Yan, Tianhua; Ma, Chunhua

    2016-04-01

    The prevalence of cognitive impairment in rheumatoid arthritis (RA) patients was increasingly serious nowadays. The purpose of the current study was to explore whether salidroside (Sal) could alleviate arthritis-induced cognition deficits and examine the relationship between the impairment and Rho/ROCK/NF-κB pathway. Collagen-induced arthritis (CIA) was established by the injection of chicken type II collagen (CII), complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA). Arthritic lesions of CIA rats were assessed by arthritis index score, swelling of paws and histological analysis. Cognitive deficits symptoms of CIA rats were monitored through Morris water maze test. The contents of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) in hippocampus and serum were significantly reduced with salidroside (20 mg/kg, 40 mg/kg) treatment compared with those in the CIA group. In parallel, we demonstrated that the expressions of RhoA, ROCK1, ROCK2, p-NF-κBp65, p-IκBα, p-IKKα and p-IKKβ were enhanced accompanying the investigation arthritis-induced cognition deficits, which were remarkably down-regulated by salidroside and confirmed by the results obtained from western blot and immunohistochemistry. LC-MS/MS results ascertained that Sal could enter into the blood and brain tissues to exhibit the protective effect on arthritis-induced cognitive dysfunction. Therefore, it was assumed that Sal might be a potential therapeutic candidate to treat arthritis-induced brain cognition deficits through the regulation of Rho/ROCK/NF-κB signaling.

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

    PubMed

    Collin, Nicolas

    2013-09-01

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

  19. Vaccine Adjuvants: Mode of Action

    PubMed Central

    De Gregorio, Ennio; Caproni, Elena; Ulmer, Jeffrey B.

    2013-01-01

    Vaccines were first introduced more than 200 years ago and have since played a key role in the reduction of morbidity and mortality caused by infectious diseases. Many of the safest and most effective vaccines in use today are based on attenuated live viruses, as they mimic a live infection without causing disease. However, it is not always practical to take this approach, such as when it may not be safe to do so (e.g., for viruses that cause chronic infections such as HIV) or may not be feasible to manufacture (e.g., for viruses that do not grow well in cell culture such as HCV). In addition, it may preferable in some cases to target immune responses toward specific antigens from the pathogen, rather than the entirety of the genome. In these cases, subunit vaccines consisting of antigens purified from the pathogen or produced by recombinant DNA technology are being developed. However, highly purified proteins are typically not inherently immunogenic, as they usually lack the means to directly stimulate the innate immune system, and often require the addition of adjuvants to enhance vaccine potency. Despite more than a century of human use, only a few adjuvants are licensed today. However many adjuvants have been tested in humans and are in advanced stages of development. Much of the early work on adjuvants discovery and development was empirical producing safe and effective products, but without a clear understanding of how they worked. Recent insight into the functioning of the innate immune system has demonstrated its important role in triggering and shaping the adaptive immune response to vaccines. PMID:23914187

  20. Herbal medicines as adjuvants for cancer therapeutics.

    PubMed

    Wang, Chong-Zhi; Calway, Tyler; Yuan, Chun-Su

    2012-01-01

    In the United States, many patients, including cancer patients, concurrently take prescription drugs and herbal supplements. Co-administration of prescription medicines and herbal supplements may have negative outcomes via pharmacodynamic and pharmacokinetic herb-drug interactions. However, multiple constituents in botanicals may also yield beneficial pharmacological activities. Botanicals could possess effective anticancer compounds that may be used as adjuvants to existing chemotherapy to improve efficacy and/or reduce drug-induced toxicity. Herbal medicines, such as ginseng, potentiated the effects of chemotherapeutic agents via synergistic activities, supported by cell cycle evaluations, apoptotic observations, and computer-based docking analysis. Since botanicals are nearly always administrated orally, the role of intestinal microbiota in metabolizing ginseng constituents is presented. Controlled clinical studies are warranted to verify the clinical utility of the botanicals in cancer chemoprevention.

  1. Delivery systems and adjuvants for oral vaccines.

    PubMed

    Lavelle, Ed C; O'Hagan, D T

    2006-11-01

    The oral route is the ideal means of delivering prophylactic and therapeutic vaccines, offering significant advantages over systemic delivery. Most notably, oral delivery is associated with simple administration and improved safety. In addition, unlike systemic immunisation, oral delivery can induce mucosal immune responses. However, the oral route of vaccine delivery is the most difficult because of the numerous barriers posed by the gastrointestinal tract. To facilitate effective immunisation with peptide and protein vaccines, antigens must be protected, uptake enhanced and the innate immune response activated. Numerous delivery systems and adjuvants have been evaluated for oral vaccine delivery, including live vectors, inert particles and bacterial toxins. Although developments in oral vaccines have been disappointing so far, in terms of the generation of products, the availability of a range of novel delivery systems offers much greater hope for the future development of improved oral vaccines.

  2. One-stage long-stem total knee arthroplasty for arthritic knees with stress fractures.

    PubMed

    Mittal, Amber; Bhosale, Pradeep B; Suryawanshi, Ashish V; Purohit, Shaligram

    2013-08-01

    PURPOSE. To evaluate the outcome of one-stage long-stem total knee arthroplasty (TKA) for patients with arthritic knees and tibiofemoral stress fractures. METHODS. Records of 11 men and 18 women aged 47 to 78 (mean, 66) years who underwent fixed-bearing posterior-stabilised TKA for osteoarthritis or rheumatoid arthritis of the knee with tibial (n=31) and femoral (n=3) stress fractures were reviewed. All the tibial fractures involved the proximal half. There were 7 associated fibular stress fractures. Of the 31 knees with tibial stress fractures, 26 and 5 manifested varus and valgus deformity, respectively. RESULTS. The mean follow-up period was 51 (range, 24-96) months. The mean tibiofemoral angle improved from 23.2 to 1.9 degrees varus. The mean Knee Society knee score improved from 38.5 (range, 15- 63) to 89.6 (range, 80-95) [p<0.05]. The mean Knee Society functional score improved from 25.5 (range, 0-40) to 86.5 (range, 60-100) [p<0.05]. All fractures were united at the last follow-up. No complications were encountered. CONCLUSION. One-stage long-stem TKA restores limb alignment and facilitates fracture healing, with excellent outcome.

  3. Distribution of lymphatic vessels in normal and arthritic human synovial tissues

    PubMed Central

    Xu, H; Edwards, J; Banerji, S; Prevo, R; Jackson, D; Athanasou, N

    2003-01-01

    Methods: Synovial tissues from 5 normal controls, 14 patients with RA, and 16 patients with OA were studied. Lymphatic vessels were identified by immunohistochemistry using antibodies directed against the lymphatic endothelial hyaluronan receptor (LYVE-1) and recognised blood vessel endothelial markers (factor VIII, CD34, CD31). Results: Lymphatic vessels were found in all zones of the normal, OA, and RA synovial membrane. Few lymphatic vessels were seen in the sublining zone in normal and OA synovium which did not show villous hypertrophy. However, in both RA synovium and OA synovium showing villous hypertrophy and a chronic inflammatory cell infiltrate, numerous lymphatic vessels were seen in all zones of the synovial membrane, including the sublining zone of the superficial subintima. Conclusions: Lymphatic vessels are present in normal and arthritic synovial tissues and are more numerous and prominent where there is oedema and an increase in inflammatory cells in the subintima, particularly in RA. This may reflect increased transport of hyaluronan and leucocyte trafficking in inflamed synovial tissues. PMID:14644866

  4. Resolvin D3 is dysregulated in arthritis and reduces arthritic inflammation

    PubMed Central

    Arnardottir, Hildur H.; Dalli, Jesmond; Norling, Lucy V.; Colas, Romain A.; Perretti, Mauro; Serhan, Charles N.

    2016-01-01

    Uncontrolled inflammation is a unifying component of many chronic inflammatory diseases, such as arthritis. Resolvins (Rv) are a new family from the endogenous specialized pro-resolving lipid mediators (SPM) that actively stimulate resolution of inflammation. Herein, using lipid mediator (LM) metabololipidomics with murine joints we found a temporal regulation of endogenous SPM during self-resolving inflammatory arthritis. The SPMs present in self-resolving arthritic joints include the D-series resolvins, e.g. Resolvin (Rv) D1, RvD2, RvD3 and RvD4. Of note, RvD3 levels were reduced in inflamed joints from mice with delayed-resolving arthritis when compared to self-resolving inflammatory arthritis. RvD3 was also reduced in serum from rheumatoid arthritis (RA) patients compared to healthy controls. RvD3 administration reduced joint leukocytes as well as paw joint eicosanoids, clinical scores and edema. Together, these findings provide evidence for dysregulated endogenous RvD3 levels in inflamed paw joints and its potent actions in reducing murine arthritis. PMID:27534559

  5. Transdermal potential and anti-arthritic efficacy of ursolic acid from niosomal gel systems.

    PubMed

    Jamal, Mahvish; Imam, Syed Sarim; Aqil, Mohd; Amir, Mohd; Mir, Shaukat R; Mujeeb, Mohd

    2015-12-01

    The aim of the present study was to optimize niosomes by experimental design for enhanced transdermal delivery of ursolic acid for the effective treatment of arthritis. The experimental design (3 factor 3 levels, Box-Behnken design) was used to study individual and combined effects of different formulation variables. The variables cholesterol (X1), span 60 (X2) and phospholipid (X3) were taken as independent factors and their effect was observed on size (Y1) entrapment efficiency (Y2), and transflux (Y3). The formulation composition with span 60 (85mg), cholesterol (12.3mg), and phospholipid (65mg) was found to fulfil requisites of optimized ursolic acid niosome formulation (URNF). URNF had shown vesicle size of 665.45nm, entrapment efficiency of 92.74% with transflux of 17.25μg/cm(2)/h. The in vivo bioactivity showed that the prepared URNF-gel was able to provide good anti-arthritic activity due to enhanced permeation of UA through the skin and results were found to be comparable to standard gel (Omni gel). The radiographical image confirmed that, the developed URNF-gel was found to be effective to treat arthritis. Thus niosomal gel of ursolic acid would be a promising alternative to conventional therapy for safe and efficient treatment of arthritis and musculoskeletal disorders.

  6. Measuring intranodal pressure and lymph viscosity to elucidate mechanisms of arthritic flare and therapeutic outcomes.

    PubMed

    Bouta, Echoe M; Wood, Ronald W; Perry, Seth W; Brown, Edward B; Ritchlin, Christopher T; Xing, Lianping; Schwarz, Edward M

    2011-12-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints; the etiology of RA is largely unknown. Recent studies in mice demonstrated that alterations in lymphatics from affected joints precede flares. Thus, we aimed to develop novel methods for measuring lymph node pressure and lymph viscosity in limbs of mice. Pressure measurements were performed by inserting a glass micropipette connected to a pressure transducer into popliteal lymph nodes (PLN) or axillary lymph nodes (ALN) of mice; subsequently, we determined that the lymphatic pressures of water were 9 and 12 cm, respectively. We are also developing methods for measuring lymph viscosity in lymphatic vessels afferent to PLN, which can be measured by multiphoton fluorescence recovery after photobleaching (MP-FRAP) of fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) injected into the hind footpad. These results demonstrate the potential of lymph node pressure and lymph viscosity measurements, and future studies to test these outcomes as biomarkers of arthritic flare are warranted.

  7. In vivo hypoxia PET imaging quantifies the severity of arthritic joint inflammation in line with overexpression of HIF and enhanced ROS generation.

    PubMed

    Fuchs, Kerstin; Kuehn, Anna; Mahling, Moritz; Guenthoer, Philipp; Hector, Andreas; Hartl, Dominik; Laufer, Stefan; Kohlhofer, Ursula; Quintanilla-Martinez, Leticia; Reischl, Gerald; Röcken, Martin; Pichler, Bernd J; Kneilling, Manfred

    2017-02-09

    Hypoxia is essential for the development of autoimmune diseases such as rheumatoid arthritis (RA) and is associated with the expression of reactive oxygen species (ROS), due to enhanced infiltration of immune cells. The aim of this study was to demonstrate the feasibility of measuring hypoxia non-invasively in vivo in arthritic ankles with positron emission tomography (PET)/magnetic resonance imaging (MRI) using the hypoxia tracers (18)F-fluoromisonidazole (FMISO) and (18)F-fluoroazomycinarabinoside (FAZA). Additionally, we quantified temporal dynamics of hypoxia and ROS stress using L-012, a ROS-sensitive chemiluminescence optical imaging (OI) probe, and analyzed the activation of hypoxia inducible factors (HIFs). Methods: Mice underwent non-invasive in vivo PET/MRI to measure hypoxia or OI to analyze ROS expression. Additionally, we performed ex vivo pimonidazole-/HIF-1α-immunohistochemistry and HIF-1α/2α-western blot/mRNA-analysis of inflamed and healthy ankles to confirm our in vivo results. Results: Mice diseased from experimental RA exhibited a 3-fold enhancement in hypoxia tracer uptake, even in the very early disease stages, and a 45-fold elevation in ROS-expression in inflamed ankles compared with the ankles of healthy controls. We further found strong correlations of our non-invasive in vivo hypoxia PET data with pimonidazole and expression of HIF-1α in arthritic ankles. The strongest hypoxia tracer uptake was observed as soon as day 3, whereas the most pronounced ROS stress was evident on day 6 after the onset of experimental RA, indicating that tissue hypoxia can precede ROS stress in RA. Conclusion: Collectively, for the first time, we have demonstrated that non-invasive measurement of hypoxia in inflammation using (18)F-FAZA/(18)F-FMISO-PET imaging represent a promising new tool for uncovering and monitoring rheumatic inflammation in vivo. Further, as hypoxic inflamed tissues are associated with overexpression of HIFs, specific inhibition of HIFs

  8. Pathogenetic difference between collagen arthritis and adjuvant arthritis

    PubMed Central

    1984-01-01

    Daily treatment with cyclosporin at a dose of 25 mg/kg for 14 d gave complete suppression of the development of collagen arthritis and adjuvant arthritis in Sprague-Dawley rats during an observation period of 45 d. To study whether the immunologic unresponsiveness produced by cyclosporin is antigen specific, we rechallenged the cyclosporin- protected rats with either type II collagen or complete Freund's adjuvant (CFA) after discontinuation of cyclosporin treatment. Type II collagen-immunized, cyclosporin-protected rats did not develop arthritis in response to reimmunization with type II collagen, but, they did develop arthritis in response to a subsequent injection of CFA. Similarly, CFA-injected, cyclosporin-protected rats showed a suppressed arthritogenic reaction in response to reinjection of CFA, whereas their response to a subsequent immunization with type II collagen was unaffected. On the other hand, the rats that were treated with cyclosporin without any prior antigenic challenge could develop arthritis in response to a subsequent injection of CFA or type II collagen after cessation of cyclosporin treatment. These results indicate that specific immunologic unresponsiveness can be induced by cyclosporin in the two experimental models of polyarthritis, collagen arthritis and adjuvant arthritis, and that there is no cross-reactivity between type II collagen and the mycobacterial cell wall components. The results further indicate that immunity to type II collagen plays a critical role in the pathogenesis of collagen arthritis but that its pathogenetic role in adjuvant arthritis is insignificant. PMID:6201583

  9. Molecular adjuvants and immunomodulators: new approaches to immunization.

    PubMed Central

    Johnson, A G

    1994-01-01

    Epitopes on microbial antigens responsible for protective immunity have begun to be identified and isolated, and their chemical structures have been determined. Ensuing knowledge of their weak immunizing capacity per se has led to an appreciation of the need for adjuvants to increase the immunogenicity of these low-molecular-weight synthetic structures. As such, a recent surge in adjuvant research has emerged. Accordingly, this review will highlight a number of those adjuvant substances whose activity in animals indicates a potential use in human vaccines. In addition, the potential of several well-defined substances, termed immunomodulators, which nonspecifically stimulate resistance of animals to multiple 50% lethal doses of microbial challenge is described. Among the most extensively characterized adjuvants of microbial origin discussed in detail are (i) the lipopolysaccharides isolated from gram-negative bacteria and their nontoxic analogs, (ii) the synthetic muramyl dipeptides and their multiple analogs, and (iii) the synthetic polyribonucleotide complexes, mimicking the interferon-inducing capacity of viruses. Discussed also are the heat-labile enterotoxin of Escherichia coli, the nonionic block copolymers, the saponins, a quinolamine derivative, and the hormone dihydroepiandrosterone. PMID:7923049

  10. Mode of action of immunological adjuvants: some physicochemical factors influencing the effectivity of polyacrylic adjuvants.

    PubMed Central

    Kreuter, J; Haenzel, I

    1978-01-01

    The adjuvant effects of different polyacrylic products and monomers were tested. Influenza vaccine was used as a model antigen. Addition of monomers resulted in a decrease in the antibody response, though adjuvant activity of the monomers should be expected according to some theories on adjuvant action. The particle size of the polymer adjuvants proved to be a very important parameter for adjuvant activity. Particles of 0.1 to 0.2 micron yielded a good adjuvant effect, whereas conglomerates or particles bigger than 0.5 micron yielded only poor or no adjuvant effects. The adjuvant effect of 0.1- to 0.2-micron particles was much more reproducible than rat of Al(OH)3. Attention is drawn to the importance of using physiochemically reproducible materials, such as polymer particles, for experimental work. Images PMID:631894

  11. 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

  12. Neisseria lactamica antigens complexed with a novel cationic adjuvant.

    PubMed

    Gaspar, Emanuelle B; Rosetti, Andreza S; Lincopan, Nilton; De Gaspari, Elizabeth

    2013-03-01

    Colonization of the nasopharynx by non-pathogenic Neisseria species, including N. lactamica, has been suggested to lead to the acquisition of natural immunity against Neisseria meningitidis in young children. The aim of this study was to identify a model complex of antigens and adjuvant for immunological preparation against N. meningitidis B, based on cross reactivity with N. lactamica outer membrane vesicles (OMV) antigens and the (DDA-BF) adjuvant. Complexes of 25 µg of OMV in 0.1 mM of DDA-BF were colloidally stable, exhibiting a mean diameter and charge optimal for antigen presentation. Immunogenicity tests for these complexes were performed in mice. A single dose of OMV/DDA-BF was sufficient to induce a (DTH) response, while the same result was achieved only after two doses of OMV/alum. In addition, to achieve total IgG levels that are similar to a single immunization with OMV/DDA-BF, it was necessary to give the mice a second dose of OMV/alum. Moreover, the antibodies induced from a single immunization with OMV/DDA-BF had an intermediate avidity, but antibodies with a similar avidity were only induced by OMV/alum after two immunizations. The use of this novel cationic adjuvant for the first time with a N. lactamica OMV preparation revealed good potential for future vaccine design.

  13. 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.

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

    PubMed

    Clegg, Christopher H; Roque, Richard; Perrone, Lucy A; Rininger, Joseph A; Bowen, Richard; Reed, Steven G

    2014-01-01

    The ongoing threat from Influenza necessitates the development of new vaccine and adjuvant technologies that can maximize vaccine immunogenicity, shorten production cycles, and increase global vaccine supply. Currently, the most successful adjuvants for Influenza vaccines are squalene-based oil-in-water emulsions. These adjuvants enhance seroprotective antibody titers to homologous and heterologous strains of virus, and augment a significant dose sparing activity that could improve vaccine manufacturing capacity. As an alternative to an emulsion, we tested a simple lipid-based aqueous formulation containing a synthetic TLR4 ligand (GLA-AF) for its ability to enhance protection against H5N1 infection. GLA-AF was very effective in adjuvanting recombinant H5 hemagglutinin antigen (rH5) in mice and was as potent as the stable emulsion, SE. Both adjuvants induced similar antibody titers using a sub-microgram dose of rH5, and both conferred complete protection against a highly pathogenic H5N1 challenge. However, GLA-AF was the superior adjuvant in ferrets. GLA-AF stimulated a broader antibody response than SE after both the prime and boost immunization with rH5, and ferrets were better protected against homologous and heterologous strains of H5N1 virus. Thus, GLA-AF is a potent emulsion-free adjuvant that warrants consideration for pandemic influenza vaccine development.

  15. A diclofenac suppository-nabumetone combination therapy for arthritic pain relief and a monitoring method for the diclofenac binding capacity of HSA site II in rheumatoid arthritis.

    PubMed

    Setoguchi, Nao; Takamura, Norito; Fujita, Ken-ichi; Ogata, Kenji; Tokunaga, Jin; Nishio, Toyotaka; Chosa, Etsuo; Arimori, Kazuhiko; Kawai, Keiichi; Yamamoto, Ryuichi

    2013-03-01

    Diclofenac suppository, a non-steroidal anti-inflammatory drug (NSAID), is used widely in rheumatoid arthritis (RA) patients with severe arthritic pain. As the binding percentage of diclofenac to serum proteins is high, its free (unbound) concentration after rectal administration is low. To increase temporarily the free concentration of diclofenac and to enhance its analgesic effect by inhibiting the protein binding of diclofenac, the analgesic effect of diclofenac was examined before and after the start of an inhibitor administration to RA patients with insufficient control of arthritic pain, and the protein binding capacity of diclofenac was evaluated. Binding experiments were performed by ultrafiltration, and arthritic pain was recorded by the face scale. Free fractions of diazepam and diclofenac were augmented by increasing 6-methoxy-2-naphthylacetic acid (6-MNA; the active metabolite of the NSAID nabumetone) concentrations. The free fraction of diazepam increased after the start of nabumetone administration to RA patients, and arthritic pain relief was observed. These results suggest that 6-MNA has an inhibitory effect on the protein binding of diclofenac and the free fraction of diazepam can be used to evaluate the binding capacity of diclofenac. It is considered that diclofenac suppository-nabumetone combination therapy and the method for protein binding monitoring by diazepam can positively benefit RA patients with insufficient control of arthritic pain.

  16. Betahistine attenuates murine collagen-induced arthritis by suppressing both inflammatory and Th17 cell responses.

    PubMed

    Tang, Kuo-Tung; Chao, Ya-Hsuan; Chen, Der-Yuan; Lim, Yun-Ping; Chen, Yi-Ming; Li, Yi-Rong; Yang, Deng-Ho; Lin, Chi-Chen

    2016-10-01

    The objective of this study was to evaluate the potential therapeutic effects of betahistine dihydrochloride (betahistine) in a collagen-induced arthritis (CIA) mouse model. CIA was induced in DBA/1 male mice by primary immunization with 100μl of emulsion containing 2mg/ml chicken type II collagen (CII) mixed with complete Freund's adjuvant (CFA) in an 1:1 ratio, and booster immunization with 100μl of emulsion containing 2mg/ml CII mixed with incomplete Freund's adjuvant (IFA) in an 1:1 ratio. Immunization was performed subcutaneously at the base of the tail. After being boosted on day 21, betahistine (1 and 5mg/kg) was orally administered daily for 2weeks. The severity of CIA was determined by arthritic scores and assessment of histopathological joint destruction. Expression of cytokines in the paw and anti-CII antibodies in the serum was evaluated by ELISA. The proliferative response against CII in the lymph node cells was measured by (3)H-thymidine incorporation assay. The frequencies of different CII specific CD4(+) T cell subsets in the lymph node were determined by flow-cytometric analysis. Betahistine treatment attenuated the severity of arthritis and reduced the levels of pro-inflammatory cytokines, including TNF-α, IL-6, IL-23 and IL-17A, in the paw tissues of CIA mice. Lymph node cells from betahistine-treated mice showed a decrease in proliferation, as well as a lower frequency of Th17 cells. In vitro, betahistine suppressed CD4(+) T cell differentiation into Th17 cells. These results indicate that betahistine is effective in suppressing both inflammatory and Th17 responses in mouse CIA and that it may have therapeutic value as an adjunct treatment for rheumatoid arthritis.

  17. RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation

    PubMed Central

    Schroder, Wayne A.; Ellis, Jonathan J.; Cumming, Helen E.; Poo, Yee Suan; Hertzog, Paul J.; Di Giallonardo, Francesca; Hueston, Linda; Le Grand, Roger; Tang, Bing; Gardner, Joy; Mahalingam, Suresh; Bird, Phillip I.

    2017-01-01

    Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme A-/- and to a lesser extent granzyme K-/-, but not granzyme B-/-, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme A-/- mice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy. Trial Registration: ClinicalTrials.gov NCT00281294 PMID:28207896

  18. Adjuvants: Classification, Modus Operandi, and Licensing

    PubMed Central

    Apostólico, Juliana de Souza

    2016-01-01

    Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations. PMID:27274998

  19. Adjuvant analgesics in cancer pain: a review.

    PubMed

    Mitra, Raj; Jones, Stephanie

    2012-02-01

    Adjuvant analgesics (co-analgesics) are medications whose primary indication is the management of a medical condition with secondary effects of analgesia. Cancer pain is multifactorial and often involves inflammatory, nociceptive, and neuropathic pain subtypes. Adjuvant analgesics used in conjunction with opioids have been found to be beneficial in the management of many cancer pain syndromes; however, they are currently underutilized. Antidepressants, anticonvulsants, local anesthetics, topical agents, steroids, bisphosphonates, and calcitonin are all adjuvants which have been shown to be effective in the management of cancer pain syndromes. When utilizing analgesic adjuvants in the treatment of cancer pain, providers must take into account the particular side effect profile of the medication. Ideally, adjuvant analgesics will be initiated at lower dosages and escalated as tolerated until efficacy or adverse effects are encountered.

  20. Vaccine adjuvants: putting innate immunity to work.

    PubMed

    Coffman, Robert L; Sher, Alan; Seder, Robert A

    2010-10-29

    Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens.

  1. Toll-Like Receptor Ligand-Based Vaccine Adjuvants Require Intact MyD88 Signaling in Antigen-Presenting Cells for Germinal Center Formation and Antibody Production

    PubMed Central

    Mosaheb, Munir M.; Reiser, Michael L.; Wetzler, Lee M.

    2017-01-01

    Vaccines are critical in the fight against infectious diseases, and immune-stimulating adjuvants are essential for enhancing vaccine efficacy. However, the precise mechanisms of action of most adjuvants are unknown. There is an urgent need for customized and adjuvant formulated vaccines against immune evading pathogens that remain a risk today. Understanding the specific role of various cell types in adjuvant-induced protective immune responses is vital for an effective vaccine design. We have investigated the role of cell-specific MyD88 signaling in vaccine adjuvant activity in vivo, using Neisserial porin B (PorB), a TLR2 ligand-based adjuvant, compared with an endosomal TLR9 ligand (CpG) and toll-like receptor (TLR)-independent (alum, MF59) adjuvants. We found that intact MyD88 signaling is essential, separately, in all three antigen-presenting cell types [B cells, macrophages, and dendritic cells (DCs)] for optimal TLR ligand-based adjuvant activity. The role of MyD88 signaling in B cell and DC in vaccine adjuvant has been previously investigated. In this study, we now demonstrate that the immune response was also reduced in mice with macrophage-specific MyD88 deletion (Mac-MyD88−/−). We demonstrate that TLR-dependent adjuvants are potent inducers of germinal center (GC) responses, but GCs are nearly absent in Mac-MyD88−/− mice following immunization with TLR-dependent adjuvants PorB or CpG, but not with TLR-independent adjuvants MF59 or alum. Our findings reveal a unique and here-to-for unrecognized importance of intact MyD88 signaling in macrophages, to allow for a robust vaccine-induced immune responses when TLR ligand-based adjuvants are used. PMID:28316602

  2. Therapeutic efficacy of undenatured type-II collagen (UC-II) in comparison to glucosamine and chondroitin in arthritic horses.

    PubMed

    Gupta, R C; Canerdy, T D; Skaggs, P; Stocker, A; Zyrkowski, G; Burke, R; Wegford, K; Goad, J T; Rohde, K; Barnett, D; DeWees, W; Bagchi, M; Bagchi, D

    2009-12-01

    The present investigation evaluated arthritic pain in horses receiving daily placebo, undenatured type II collagen (UC-II) at 320, 480, or 640 mg (providing 80, 120, and 160 mg active UC-II, respectively), and glucosamine and chondroitin (5.4 and 1.8 g, respectively, bid for the first month, and thereafter once daily) for 150 days. Horses were evaluated for overall pain, pain upon limb manipulation, physical examination, and liver and kidney functions. Evaluation of overall pain was based upon a consistent observation of all subjects during a walk and a trot in the same pattern on the same surface. Pain upon limb manipulation was conducted after the walk and trot. It consisted of placing the affected joint in severe flexion for a period of 60 sec. The limb was then placed to the ground and the animal trotted off. The response to the flexion test was then noted with the first couple of strides the animal took. Flexion test was consistent with determining clinically the degree of osteoarthritis in a joint. Horses receiving placebo showed no change in arthritic condition, while those receiving 320 or 480 or 640 mg UC-II exhibited significant reduction in arthritic pain (P < 0.05). UC-II at 480 or 640 mg dose provided equal effects, and therefore, 480 mg dose was considered optimal. With this dose, reduction in overall pain was from 5.7 +/- 0.42 (100%) to 0.7 +/- 0.42 (12%); and in pain upon limb manipulation from 2.35 +/- 0.37 (100%) to 0.52 +/- 0.18 (22%). Although glucosamine and chondroitin treated group showed significant (P < 0.05) reduction in pain compared with pretreated values, the efficacy was less compared with that observed with UC-II. In fact, UC-II at 480 or 640 mg dose was found to be more effective than glucosamine and chondroitin in arthritic horses. Clinical condition (body weight, body temperature, respiration rate, and pulse rate), and liver (bilirubin, GGT, and ALP) and kidney (BUN and creatinine) functions remained unchanged, suggesting that

  3. Evaluation of mucoadhesive carrier adjuvant: toward an oral anthrax vaccine.

    PubMed

    Mangal, Sharad; Pawar, Dilip; Agrawal, Udita; Jain, Arvind K; Vyas, Suresh P

    2014-02-01

    The aim of present study was to evaluate the potential of mucoadhesive alginate-coated chitosan microparticles (A-CHMp) for oral vaccine against anthrax. The zeta potential of A-CHMp was -29.7 mV, and alginate coating could prevent the burst release of antigen in simulated gastric fluid. The results indicated that A-CHMp was mucoadhesive in nature and transported it to the peyer's patch upon oral delivery. The immunization studies indicated that A-CHMp resulted in the induction of potent systemic and mucosal immune responses, whereas alum-adjuvanted rPA could induce only systemic immune response. Thus, A-CHMp represents a promising acid carrier adjuvant for oral immunization against anthrax.

  4. Aging-induced changes in 24-h rhythms of mitogenic responses, lymphocyte subset populations and neurotransmitter and amino acid content in rat submaxillary lymph nodes during Freund's adjuvant arthritis.

    PubMed

    Bonacho, M G; Cardinali, D P; Castrillón, P; Cutrera, R A; Esquifino, A I

    2001-02-01

    In young (two months) and aged (18 months) male rats injected s.c. with Freund's adjuvant or adjuvant's vehicle 18 days earlier, 24-h variations in mitogenic responses, lymphocyte subsets and monoamine and amino acid content were examined in submaxillary lymph nodes. Mitogenic responses to concanavalin A (Con A) and lipopolysaccharide (LPS) were higher during the light phase of daily photoperiod. Old rats exhibited a suppressed or impaired mitogenic response to Con A but not to LPS. Acrophases of 24-h rhythm in lymphocyte subset populations in submaxillary lymph nodes were: 18:37-19:44h (B cells), 09:00-10:08h (T and CD4(+) cells) and 12:19-15:58h (CD8(+) cells). Aging augmented B cells and decreased T, CD4(+) and CD8(+) cells. Significant correlations were found between Con A activity and T cells, between lymph node 5HT content and B, T and CD8(+) lymphocytes, and between lymph node 5HT and taurine and GABA content. Aging increased lymph node 5HT content but did not modify NE content. Lymph node concentration of aspartate, glutamate and taurine was higher at night while that of GABA attained peak values at late afternoon. Old rats injected with Freund's adjuvant showed a higher mean value (glutamate) and smaller amplitude (glutamate, taurine) than their respective young controls. The results further document the effects of aging on the chronobiology of the immune system.

  5. Investigation of the role of endosomal Toll-like receptors in murine collagen-induced arthritis reveals a potential role for TLR7 in disease maintenance

    PubMed Central

    2012-01-01

    Introduction Endosomal toll-like receptors (TLRs) have recently emerged as potential contributors to the inflammation observed in human and rodent models of rheumatoid arthritis (RA). This study aims to evaluate the role of endosomal TLRs and in particular TLR7 in the murine collagen induced arthritis (CIA) model. Methods CIA was induced by injection of collagen in complete Freund's adjuvant. To investigate the effect of endosomal TLRs in the CIA model, mianserin was administered daily from the day of disease onset. The specific role of TLR7 was examined by inducing CIA in TLR7-deficient mice. Disease progression was assessed by measuring clinical score, paw swelling, serum anti-collagen antibodies histological parameters, cytokine production and the percentage of T regulatory (Treg) cells. Results Therapeutic administration of mianserin to arthritic animals demonstrated a highly protective effect on paw swelling and joint destruction. TLR7-/- mice developed a mild arthritis, where the clinical score and paw swelling were significantly compromised in comparison to the control group. The amelioration of arthritis by mianserin and TLR7 deficiency both corresponded with a reduction in IL-17 responses, histological and clinical scores, and paw swelling. Conclusions These data highlight the potential role for endosomal TLRs in the maintenance of inflammation in RA and support the concept of a role for TLR7 in experimental arthritis models. This study also illustrates the potential benefit that may be afforded by therapeutically inhibiting the endosomal TLRs in RA. PMID:22691272

  6. Potent response of QS-21 as a vaccine adjuvant in the skin when delivered with the Nanopatch, resulted in adjuvant dose sparing

    PubMed Central

    Ng, Hwee-Ing; Fernando, Germain J. P.; Depelsenaire, Alexandra C. I.; Kendall, Mark A. F.

    2016-01-01

    Adjuvants play a key role in boosting immunogenicity of vaccines, particularly for subunit protein vaccines. In this study we investigated the induction of antibody response against trivalent influenza subunit protein antigen and a saponin adjuvant, QS-21. Clinical trials of QS-21 have demonstrated the safety but, also a need of high dose for optimal immunity, which could possibly reduce patient acceptability. Here, we proposed the use of a skin delivery technology – the Nanopatch – to reduce both adjuvant and antigen dose but also retain its immune stimulating effects when compared to the conventional needle and syringe intramuscular (IM) delivery. We have demonstrated that Nanopatch delivery to skin requires only 1/100th of the IM antigen dose to induce equivalent humoral response. QS-21 enhanced humoral response in both skin and muscle route. Additionally, Nanopatch has demonstrated 30-fold adjuvant QS-21 dose sparing while retaining immune stimulating effects compared to IM. QS-21 induced localised, controlled cell death in the skin, suggesting that the danger signals released from dead cells contributed to the enhanced immunogenicity. Taken together, these findings demonstrated the suitability of reduced dose of QS-21 and the antigen using the Nanopatch to enhance humoral responses, and the potential to increase patient acceptability of QS-21 adjuvant. PMID:27404789

  7. Potent response of QS-21 as a vaccine adjuvant in the skin when delivered with the Nanopatch, resulted in adjuvant dose sparing.

    PubMed

    Ng, Hwee-Ing; Fernando, Germain J P; Depelsenaire, Alexandra C I; Kendall, Mark A F

    2016-07-11

    Adjuvants play a key role in boosting immunogenicity of vaccines, particularly for subunit protein vaccines. In this study we investigated the induction of antibody response against trivalent influenza subunit protein antigen and a saponin adjuvant, QS-21. Clinical trials of QS-21 have demonstrated the safety but, also a need of high dose for optimal immunity, which could possibly reduce patient acceptability. Here, we proposed the use of a skin delivery technology - the Nanopatch - to reduce both adjuvant and antigen dose but also retain its immune stimulating effects when compared to the conventional needle and syringe intramuscular (IM) delivery. We have demonstrated that Nanopatch delivery to skin requires only 1/100(th) of the IM antigen dose to induce equivalent humoral response. QS-21 enhanced humoral response in both skin and muscle route. Additionally, Nanopatch has demonstrated 30-fold adjuvant QS-21 dose sparing while retaining immune stimulating effects compared to IM. QS-21 induced localised, controlled cell death in the skin, suggesting that the danger signals released from dead cells contributed to the enhanced immunogenicity. Taken together, these findings demonstrated the suitability of reduced dose of QS-21 and the antigen using the Nanopatch to enhance humoral responses, and the potential to increase patient acceptability of QS-21 adjuvant.

  8. Adjuvants are Key Factors for the Development of Future Vaccines: Lessons from the Finlay Adjuvant Platform

    PubMed Central

    Pérez, Oliver; Romeu, Belkis; Cabrera, Osmir; González, Elizabeth; Batista-Duharte, Alexander; Labrada, Alexis; Pérez, Rocmira; Reyes, Laura M.; Ramírez, Wendy; Sifontes, Sergio; Fernández, Nelson; Lastre, Miriam

    2013-01-01

    The development of effective vaccines against neglected diseases, especially those associated with poverty and social deprivation, is urgently needed. Modern vaccine technologies and a better understanding of the immune response have provided scientists with the tools for rational and safer design of subunit vaccines. Often, however, subunit vaccines do not elicit strong immune responses, highlighting the need to incorporate better adjuvants; this step therefore becomes a key factor for vaccine development. In this review we outline some key features of modern vaccinology that are linked with the development of better adjuvants. In line with the increased desire to obtain novel adjuvants for future vaccines, the Finlay Adjuvant Platform offers a novel approach for the development of new and effective adjuvants. The Finlay Adjuvants (AFs), AFPL (proteoliposome), and AFCo (cochleate), were initially designed for parenteral and mucosal applications, and constitute potent adjuvants for the induction of Th1 responses against several antigens. This review summarizes the status of the Finlay technology in producing promising adjuvants for unsolved-vaccine diseases including mucosal approaches and therapeutic vaccines. Ideas related to adjuvant classification, adjuvant selection, and their possible influence on innate recognition via multiple toll-like receptors are also discussed. PMID:24348475

  9. Adjuvants are Key Factors for the Development of Future Vaccines: Lessons from the Finlay Adjuvant Platform.

    PubMed

    Pérez, Oliver; Romeu, Belkis; Cabrera, Osmir; González, Elizabeth; Batista-Duharte, Alexander; Labrada, Alexis; Pérez, Rocmira; Reyes, Laura M; Ramírez, Wendy; Sifontes, Sergio; Fernández, Nelson; Lastre, Miriam

    2013-12-02

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

  10. Particulate Adjuvant and Innate Immunity: Past Achievements, Present Findings, and Future Prospects

    PubMed Central

    Kuroda, Etsushi; Coban, Cevayir

    2013-01-01

    Particulates and crystals stimulate the immune system to induce inflammatory responses. Several nanometer- to micrometer-sized particulates, such as particle matter 2.5 (PM2.5), diesel particles, and sand dust, induce pulmonary inflammation and allergic asthma. Conversely, nanometer- to micrometer-sized crystal, sphere, and hydrogel forms of aluminum salts (referred to as “alum”) have been used as vaccine adjuvants to enhance antibody responses in animals and humans. Although most of these particulates induce type-2 immune responses in vivo, the molecular and immunological mechanisms of action as a vaccine adjuvant are poorly understood. In this review, recent advances in particulate adjuvant research from the standpoint of innate immune responses are discussed. PMID:23570316

  11. Safety of vaccine adjuvants: focus on autoimmunity.

    PubMed

    van der Laan, Jan Willem; Gould, Sarah; Tanir, Jennifer Y

    2015-03-24

    Questions have been recently raised regarding the safety of vaccine adjuvants, particularly in relation to autoimmunity or autoimmune disease(s)/disorder(s) (AID). The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) formed a scientific committee and convened a 2-day workshop, consisting of technical experts from around the world representing academia, government regulatory agencies, and industry, to investigate and openly discuss the issues around adjuvant safety in vaccines. The types of adjuvants considered included oil-in-water emulsions and toll-like receptor (TLR) agonists. The state of science around the use of animal models and biomarkers for the evaluation and prediction of AID were also discussed. Following extensive literature reviews by the HESI committee, and presentations by experts at the workshop, several key points were identified, including the value of animal models used to study autoimmunity and AID toward studying novel vaccine adjuvants; whether there is scientific evidence indicating an intrinsic risk of autoimmunity and AID with adjuvants, or a higher risk resulting from the mechanism of action; and if there is compelling clinical data linking adjuvants and AID. The tripartite group of experts concluded that there is no compelling evidence supporting the association of vaccine adjuvants with autoimmunity signals. Additionally, it is recommended that future research on the potential effects of vaccine adjuvants on AID should consider carefully the experimental design in animal models particularly if they are to be used in any risk assessment, as an improper design and model could result in misleading information. Finally, studies on the mechanistic aspects and potential biomarkers related to adjuvants and autoimmunity phenomena could be developed.

  12. Immunostimulatory Oligodeoxynucleotides Containing the CpG Motif are Effective as Immune Adjuvants in Tumor Antigen Immunization

    NASA Astrophysics Data System (ADS)

    Weiner, George J.; Liu, Hsin-Ming; Wooldridge, James E.; Dahle, Christopher E.; Krieg, Arthur M.

    1997-09-01

    Recent advances in our understanding of the immune response are allowing for the logical design of new approaches to cancer immunization. One area of interest is the development of new immune adjuvants. Immunostimulatory oligodeoxynucleotides containing the CpG motif (CpG ODN) can induce production of a wide variety of cytokines and activate B cells, monocytes, dendritic cells, and NK cells. Using the 38C13 B cell lymphoma model, we assessed whether CpG ODN can function as immune adjuvants in tumor antigen immunization. The idiotype served as the tumor antigen. Select CpG ODN were as effective as complete Freund's adjuvant at inducing an antigen-specific antibody response but were associated with less toxicity. These CpG ODN induced a higher titer of antigen-specific IgG2a than did complete Freund's adjuvant, suggesting an enhanced TH1 response. Mice immunized with CpG ODN as an adjuvant were protected from tumor challenge to a degree similar to that seen in mice immunized with complete Freund's adjuvant. We conclude that CpG ODN are effective as immune adjuvants and are attractive as part of a tumor immunization strategy.

  13. Anti-inflammatory and anti-arthritic activity of a methanol extract from Vitellaria paradoxa stem bark

    PubMed Central

    Foyet, Harquin Simplice; Tsala, David Emery; Zogo Essono Bodo, J.C; Carine, Azanfack Name; Heroyne, Lissia Toussoumna; Oben, Eyong Kenneth

    2015-01-01

    Background: Vitellaria paradoxa is a traditional medicinal plant of Cameroon. Several studies on this plant have focused on the cosmetic profile of its fruits. The present study focuses on the anti-inflammatory potency of stem barks extract of this plant. Objective: The objective was to evaluate the effect of methanolic extract of V. paradoxa (VPME) stem barks on inflammatory response in rats. Materials and Methods: Anti-inflammatory effects of VPME were evaluated in acute and chronic (28 days) inflammation induced in Wistar albino rats. The effects on hyperalgesia and locomotors activity were also quantified. The relative weight of lymphoid organs was obtained as well as some hematological parameters. Results: In the carrageenan-induced inflammation, VPME (75 mg/kg) exhibited a significant (66.67%) inhibition after 1 h. On the complete Freund's adjuvant-induced rheumatoid arthritis, VPME showed a significant protective effect with 8.12% inflammation against 25.00% for the control group after 2 days of the treatment. The extract (75 and 150 mg/kg) significantly reduced the score of arthritis with a maximum obtained on day 19th of the experimentation. There was a significant increase in the reaction time of rats on the hot plate as well as the exploratory activities of the animals in the open field. This extract significantly prevented weight, hemoglobin and red blood cells losses, and spleen hypertrophy. A protective action against skin destruction and cartilage erosion was evident. Liquid chromatography-mass spectrometry analysis of the extract revealed the presence of catechins. Conclusions: These findings suggested that V. paradoxa may contribute to the reduction of the inflammatory response. PMID:26692752

  14. [Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].

    PubMed

    Kobiyama, Kouji; Ishii, Ken J

    2015-09-01

    Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy.

  15. Cyclic GMP-AMP Displays Mucosal Adjuvant Activity in Mice

    PubMed Central

    Škrnjug, Ivana

    2014-01-01

    The recently discovered mammalian enzyme cyclic GMP-AMP synthase produces cyclic GMP-AMP (cGAMP) after being activated by pathogen-derived cytosolic double stranded DNA. The product can stimulate STING-dependent interferon type I signaling. Here, we explore the efficacy of cGAMP as a mucosal adjuvant in mice. We show that cGAMP can enhance the adaptive immune response to the model antigen ovalbumin. It promotes antigen specific IgG and a balanced Th1/Th2 lymphocyte response in immunized mice. A characteristic of the cGAMP-induced immune response is the slightly reduced induction of interleukin-17 as a hallmark of Th17 activity – a distinct feature that is not observed with other cyclic di-nucleotide adjuvants. We further characterize the innate immune stimulation activity in vitro on murine bone marrow-derived dendritic cells and human dendritic cells. The observed results suggest the consideration of cGAMP as a candidate mucosal adjuvant for human vaccines. PMID:25295996

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

    PubMed Central

    Sun, Li-Juan; Guo, Xue; Tian, Tian; Zhang, Jian; Guo, Qi-Yuan; Li, Xue; Guo, Li-Jun; Che, Jin; Wang, Bing; Zhang, Hui

    2017-01-01

    Intranasal vaccination is more potent than parenteral injection for the prevention of influenza. However, because the poor efficiency of antigen uptake across the nasal mucosa is a key issue, immunostimulatory adjuvants are essential for intranasal vaccines. The immunomodulator mannatide or polyactin (PA) has been used for the clinical treatment of impaired immunity in China, but its adjuvant effect on an inactivated trivalent influenza vaccine (ITIV) via intranasal vaccination is unclear. To explore the adjuvant effect of PA, an inactivated trivalent influenza virus with or without PA or MF59 was instilled intranasally once a week in BALB/c mice. Humoral immunity was assessed by both the ELISA and hemagglutination inhibition (HI) methods using antigen-specific antibodies. Splenic lymphocyte proliferation and the IFN-γ level were measured to evaluate cell-mediated immunity. The post-vaccination serum HI antibody geometric mean titers (GMTs) for the H1N1 and H3N2 strains, antigen-specific serum IgG and IgA GMTs, mucosal SIgA GMT, splenic lymphocyte proliferation, and IFN-γ were significantly increased in the high-dose PA-adjuvanted vaccine group. The seroconversion rate and the mucosal response for the H3N2 strain were significantly elevated after high-dose PA administration. These adjuvant effects of high-dose PA for the influenza vaccine were comparable with those of the MF59 adjuvant, and abnormal signs or pathological changes were not found in the evaluated organs. In conclusion, PA is a novel mucosal adjuvant for intranasal vaccination with the ITIV that has safe and effective mucosal adjuvanticity in mice and successfully induces both serum and mucosal antibody responses and a cell-mediated response. PMID:28052136

  17. 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.

  18. 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.

  19. Vaccines with Aluminum-Containing Adjuvants: Optimizing Vaccine Efficacy and Thermal Stability

    PubMed Central

    Clapp, Tanya; Siebert, Paul; Chen, Dexiang; Braun, LaToya Jones

    2011-01-01

    Aluminum-containing adjuvants have been used to enhance the immune response against killed, inactivated and subunit antigens for over seven decades. Nevertheless, we are only beginning to gain important insight as to what may be some very fundamental parameters for optimizing their use. For example, there is evidence that the conventional approach of maximizing antigen binding (amount and/or strength) may not result in an optimal immune response. Adsorption of antigen onto the adjuvant has recently been suggested to decrease the thermal stability of some antigens; however, whether adsorption-induced alterations to the structure and/or stability of the antigen have consequences for the elicited immune response is unclear. Finally, the thermal stability of vaccines with aluminum-containing adjuvants is not robust. Optimizing the stability of these vaccines requires an understanding of the freeze sensitivity of the adjuvant, freeze and heat sensitivity of the antigen in the presence of the adjuvant, and perhaps most importantly, how (or whether) various approaches to formulation can be used to address these instabilities. This review attempts to summarize recent findings regarding issues that may dictate the success of vaccines with aluminum-containing adjuvants. PMID:20740674

  20. Mesoporous silica nanoparticles as antigen carriers and adjuvants for vaccine delivery

    NASA Astrophysics Data System (ADS)

    Mody, Karishma T.; Popat, Amirali; Mahony, Donna; Cavallaro, Antonino S.; Yu, Chengzhong; Mitter, Neena

    2013-05-01

    Vaccines have been at the forefront of improving human health for over two centuries. The challenges faced in developing effective vaccines flow from complexities associated with the immune system and requirement of an efficient and safe adjuvant to induce a strong adaptive immune response. Development of an efficient vaccine formulation requires careful selection of a potent antigen, efficient adjuvant and route of delivery. Adjuvants are immunological agents that activate the antigen presenting cells (APCs) and elicit a strong immune response. In the past decade, the use of mesoporous silica nanoparticles (MSNs) has gained significant attention as potential delivery vehicles for various biomolecules. In this review, we aim to highlight the potential of MSNs as vaccine delivery vehicles and their ability to act as adjuvants. We have provided an overview on the latest progress on synthesis, adsorption and release kinetics and biocompatibility of MSNs as next generation antigen carriers and adjuvants. A comprehensive summary on the ability of MSNs to deliver antigens and elicit both humoral and cellular immune responses is provided. Finally, we give insight on fundamental challenges and some future prospects of these nanoparticles as adjuvants.

  1. 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

  2. Targeted vaccine adjuvants based on modified cholera toxin.

    PubMed

    Lycke, Nils

    2005-09-01

    The present review describes immunomodulation with targeted adjuvants that will allow for the development of efficacious mucosal vaccines. We have studied cholera toxin (CT) and derivatives thereof, to rationally design vaccine adjuvant vectors that are both highly efficacious as well as safe and non-toxic. Two strategies were exploited; the first using CT or the enzymatically inactive receptor-binding B-subunit of CT (CTB) and the second, using CTA1 or an enzymatically inactive mutant CTA1R7K., that was linked, in a fusion protein, to the B-cell targeting moiety, DD, from Staphylococcus areus proteinA. Our studies provide compelling evidence that delivery of Ag in the absence of ADP-ribosylation can promote tolerance, whereas, ADP-ribosyltransferase-active conjugates, prevent tolerance but induce IgA immunity. Our analysis revealed unique subsets of mucosal and systemic DC that appeared to be responsible for the ADP-ribosyltransferase sensitive dichotomy between tolerance and IgA immunity. Whether targeting of B cells suffice for tolerance-induction or requires participation of DCs, is at present an unresolved issue. Nevertheless, enzymatic modulation differentiates and matures the DC to promote CD4 T cell help for IgA B cell development. Ag-presentation in the absence of enzyme, as seen with CTA1R7K-DD, expands specific T cells to a similar extent as enzymatically active CTA1-DD, but fails to recruit help for germinal center expansion of activated B cells. We have given special attention to the genes that adjuvants turn on using Affymetrix technology. In particular, modulation of the expression of co-stimulatory molecules on the targeted APC; CD80, CD86, CD83 and B7RP-1, play important roles for the effect of the ADP-ribosylating CTA1-based adjuvants for the development of tolerance or active IgA immunity.

  3. Freund's adjuvants: relationship of arthritogenicity and adjuvanticity in rats to vehicle composition

    PubMed Central

    Whitehouse, M. W.; Orr, K. J.; Beck, Frances W. J.; Pearson, C. M.

    1974-01-01

    Over a hundred compounds and natural materials were examined for their ability to induce arthritis in rats when mixed with heat-killed delipidated Mycobacteria tuberculosis. Many of these materials were also assessed for (CMI) adjuvant activity by their ability to induce allergic encephalomyelitis (EAE) in rats when mixed with guinea-pig spinal cord, both with and without added M. tuberculosis. Cyclization and/or the presence of oxygen atoms, or double bonds reduced (or abolished) the arthritogenic potential and adjuvanticity of alkanes>C10. Esters/triglycerides of fatty acids >C12, retinol acetate (not palmitate) and vitamins E and K showed co-arthritogenic and adjuvant activity. Other active lipids included squalene and cholesterol oleate, which are both present in human sebum. Sebaceous lipids may therefore perhaps function as natural adjuvants if resorbed during abrasion and infection. Squalane (perhydrosqualene), pristane and hexadecane were excellent substitutes for mineral oil in preparing arthritogenic adjuvants from various mycobacteria, C. rubrum and N. asteroides. These oily compounds were also very effective adjuvants per se, in the absence of bacterial material or emulsifier, for inducing EAE in Lewis rats. PMID:4214125

  4. [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.

  5. Non-Specific Immunotherapies and Adjuvants

    MedlinePlus

    ... and Side Effects Treatment Types Immunotherapy Non-specific cancer immunotherapies and adjuvants Non-specific immunotherapies don’t target ... This makes BCG useful as a form of cancer immunotherapy. BCG was one of the earliest immunotherapies used ...

  6. Extended Adjuvant Therapy for Breast Cancer

    Cancer.gov

    An NCI Cancer Currents blog on findings from a recent clinical trial which showed that extending adjuvant therapy with an aromatase inhibitor can have important benefits for some women with early-stage cancer.

  7. Adjuvant Bisphosphonates for Postmenopausal Breast Cancer

    Cancer.gov

    A summary of a meta-analysis of randomized trials of bisphosphonates as adjuvant therapy for women with early-stage breast cancer that shows the drugs can reduce the rate of disease recurrence in bone.

  8. Modulation of HIV-1 immunity by adjuvants

    PubMed Central

    Moody, M. Anthony

    2014-01-01

    Purpose of review To summarize the role of adjuvants in eliciting desirable antibody responses against HIV-1 with particular emphasis on both historical context and recent developments. Recent findings Increased understanding of the role of pattern recognition receptors such as Toll-like receptors in recruiting and directing the immune system has increased the variety of adjuvant formulations being tested in animal models and humans. Across all vaccine platforms, adjuvant formulations have been shown to enhance desirable immune responses such as higher antibody titers and increased functional activity. Although no vaccine formulation has yet succeeded in eliciting broad neutralizing antibodies against HIV-1, the ability of adjuvants to direct the immune response to immunogens suggests they will be critically important in any successful HIV-1 vaccine. Summary The parallel development of adjuvants along with better HIV-1 immunogens will be needed for a successful AIDS vaccine. Additional comparative testing will be required to determine the optimal adjuvant and immunogen regimen that can elicit antibody responses capable of blocking HIV-1 transmission. PMID:24670321

  9. Adjuvant therapy after surgical stone management.

    PubMed

    Ferrandino, Michael N; Monga, Manoj; Preminger, Glenn M

    2009-01-01

    The aim of this article was to review the most widely researched adjuvant medical therapies for the surgical management of urolithiasis. Articles were identified and reviewed from PubMed and Medline databases with MeSH headings focusing on the various surgical treatments of urolithiasis and adjuvant therapy. Additional articles were retrieved from references and conference proceedings. Surgical treatments reviewed included shockwave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy. Adjuvant therapy was considered medical or complementary therapy as an adjunct to these surgical interventions. Adjuvant therapy for the surgical management of urolithiasis has been documented to increase stone-free rates, reduce stone remission rates, prevent renal damage, and decrease postoperative morbidity. A variety of agents have been studied, ranging from antioxidants to alpha-blockers and to alkalinizing agents. Additionally, there is increasing interest in complementary adjuvant therapy (ie, acupuncture). Adjuvant therapy is a fertile area for research in the surgical management of urolithiasis. The optimal agents have yet to be determined and therefore further investigation is warranted and necessary.

  10. Applications of nanomaterials as vaccine adjuvants.

    PubMed

    Zhu, Motao; Wang, Rongfu; Nie, Guangjun

    2014-01-01

    Vaccine adjuvants are applied to amplify the recipient's specific immune responses against pathogen infection or malignancy. A new generation of adjuvants is being developed to meet the demands for more potent antigen-specific responses, specific types of immune responses, and a high margin of safety. Nanotechnology provides a multifunctional stage for the integration of desired adjuvant activities performed by the building blocks of tailor-designed nanoparticles. Using nanomaterials for antigen delivery can provide high bioavailability, sustained and controlled release profiles, and targeting and imaging properties resulting from manipulation of the nanomaterials' physicochemical properties. Moreover, the inherent immune-regulating activity of particular nanomaterials can further promote and shape the cellular and humoral immune responses toward desired types. The combination of both the delivery function and immunomodulatory effect of nanomaterials as adjuvants is thought to largely benefit the immune outcomes of vaccination. In this review, we will address the current achievements of nanotechnology in the development of novel adjuvants. The potential mechanisms by which nanomaterials impact the immune responses to a vaccine and how physicochemical properties, including size, surface charge and surface modification, impact their resulting immunological outcomes will be discussed. This review aims to provide concentrated information to promote new insights for the development of novel vaccine adjuvants.

  11. Exercise as an Adjuvant Therapy for Hematopoietic Stem Cell Mobilization

    PubMed Central

    Emmons, Russell; Niemiro, Grace M.; De Lisio, Michael

    2016-01-01

    Hematopoietic stem cell transplant (HSCT) using mobilized peripheral blood hematopoietic stem cells (HSPCs) is the only curative strategy for many patients suffering from hematological malignancies. HSPC collection protocols rely on pharmacological agents to mobilize HSPCs to peripheral blood. Limitations including variable donor responses and long dosing protocols merit further investigations into adjuvant therapies to enhance the efficiency of HSPCs collection. Exercise, a safe and feasible intervention in patients undergoing HSCT, has been previously shown to robustly stimulate HSPC mobilization from the bone marrow. Exercise-induced HSPC mobilization is transient limiting its current clinical potential. Thus, a deeper investigation of the mechanisms responsible for exercise-induced HSPC mobilization and the factors responsible for removal of HSPCs from circulation following exercise is warranted. The present review will describe current research on exercise and HSPC mobilization, outline the potential mechanisms responsible for exercise-induced HSPC mobilization, and highlight potential sites for HSPC homing following exercise. We also outline current barriers to the implementation of exercise as an adjuvant therapy for HSPC mobilization and suggest potential strategies to overcome these barriers. PMID:27123008

  12. 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.

  13. Formulation, High Throughput In Vitro Screening and In Vivo Functional Characterization of Nanoemulsion-Based Intranasal Vaccine Adjuvants

    PubMed Central

    Wong, Pamela T.; Leroueil, Pascale R.; Smith, Douglas M.; Ciotti, Susan; Bielinska, Anna U.; Janczak, Katarzyna W.; Mullen, Catherine H.; Groom, Jeffrey V.; Taylor, Erin M.; Passmore, Crystal; Makidon, Paul E.; O’Konek, Jessica J.; Myc, Andrzej; Hamouda, Tarek; Baker, James R.

    2015-01-01

    Vaccine adjuvants have been reported to induce both mucosal and systemic immunity when applied to mucosal surfaces and this dual response appears important for protection against certain pathogens. Despite the potential advantages, however, no mucosal adjuvants are currently approved for human use. Evaluating compounds as mucosal adjuvants is a slow and costly process due to the need for lengthy animal immunogenicity studies. We have constructed a library of 112 intranasal adjuvant candidate formulations consisting of oil-in-water nanoemulsions that contain various cationic and nonionic surfactants. To facilitate adjuvant development we first evaluated this library in a series of high-throughput, in vitro assays for activities associated with innate and adaptive immune activation in vivo. These in vitro assays screened for the ability of the adjuvant to bind to mucin, induce cytotoxicity, facilitate antigen uptake in epithelial and dendritic cells, and activate cellular pathways. We then sought to determine how these parameters related to adjuvant activity in vivo. While the in vitro assays alone were not enough to predict the in vivo adjuvant activity completely, several interesting relationships were found with immune responses in mice. Furthermore, by varying the physicochemical properties of the surfactant components (charge, surfactant polar head size and hydrophobicity) and the surfactant blend ratio of the formulations, the strength and type of the immune response generated (TH1, TH2, TH17) could be modulated. These findings suggest the possibility of using high-throughput screens to aid in the design of custom adjuvants with unique immunological profiles to match specific mucosal vaccine applications. PMID:25962136

  14. Adjuvant effects of saponins on animal immune responses*

    PubMed Central

    Rajput, Zahid Iqbal; Hu, Song-hua; Xiao, Chen-wen; Arijo, Abdullah G.

    2007-01-01

    Vaccines require optimal adjuvants including immunopotentiator and delivery systems to offer long term protection from infectious diseases in animals and man. Initially it was believed that adjuvants are responsible for promoting strong and sustainable antibody responses. Now it has been shown that adjuvants influence the isotype and avidity of antibody and also affect the properties of cell-mediated immunity. Mostly oil emulsions, lipopolysaccharides, polymers, saponins, liposomes, cytokines, ISCOMs (immunostimulating complexes), Freund’s complete adjuvant, Freund’s incomplete adjuvant, alums, bacterial toxins etc., are common adjuvants under investigation. Saponin based adjuvants have the ability to stimulate the cell mediated immune system as well as to enhance antibody production and have the advantage that only a low dose is needed for adjuvant activity. In the present study the importance of adjuvants, their role and the effect of saponin in immune system is reviewed. PMID:17323426

  15. Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle.

    PubMed

    Granado, Miriam; Priego, Teresa; Martín, Ana I; Villanúa, Maria Angeles; López-Calderón, Asunción

    2005-12-01

    Chronic arthritis is a catabolic state associated with an inhibition of the IGF system and a decrease in body weight. Cachexia and muscular wasting is secondary to protein degradation by the ubiquitin-proteasome pathway. The aim of this work was to analyze the effect of adjuvant-induced arthritis on the muscle-specific ubiquitin ligases muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) as well as on IGF-I and IGF-binding protein-5 (IGFBP-5) gene expression in the skeletal muscle. We also studied whether the synthetic ghrelin receptor agonist, growth hormone releasing peptide-2 (GHRP-2), was able to prevent arthritis-induced changes in the skeletal muscle. Arthritis induced an increase in MuRF1, MAFbx (P < 0.01), and tumor necrosis factor (TNF)-alpha mRNA (P < 0.05) in the skeletal muscle. Arthritis decreased the serum IGF-I and its gene expression in the liver (P < 0.01), whereas it increased IGF-I and IGFBP-5 gene expression in the skeletal muscle (P < 0.01). Administration of GHRP-2 for 8 days prevented the arthritis-induced increase in muscular MuRF1, MAFbx, and TNF-alpha gene expression. GHRP-2 treatment increased the serum concentrations of IGF-I and the IGF-I mRNA in the liver and in the cardiac muscle and decreased muscular IGFBP-5 mRNA both in control and in arthritic rats (P < 0.05). GHRP-2 treatment increased muscular IGF-I mRNA in control rats (P < 0.01), but it did not modify the muscular IGF-I gene expression in arthritic rats. These data indicate that arthritis induces an increase in the activity of the ubiquitin-proteasome proteolytic pathway that is prevented by GHRP-2 administration. The parallel changes in muscular IGFBP-5 and TNF-alpha gene expression with the ubiquitin ligases suggest that they can participate in skeletal muscle alterations during chronic arthritis.

  16. Oral vaccination against diphtheria using polyacryl starch microparticles as adjuvant.

    PubMed

    Rydell, Niclas; Sjöholm, Ingvar

    2004-03-12

    Oral vaccination offers the advantage of eliciting both a mucosal and a systemic immune response. This study investigated the use of polyacryl starch microparticles as adjuvant for oral vaccination against diphtheria. Diphtheria toxin or cross-reacting material (CRM197) were covalently conjugated to the microparticles and fed to mice by oral gavage. Investigation of formaldehyde treatment as a means of either detoxifying (diphtheria toxin) or stabilising (CRM197) these formulations were also made. We show that all our formulations given orally or parenterally to mice induced a strong systemic immune response. Only formulations given orally induced a mucosal IgA-response. Furthermore, our formulations given parenterally or orally induced a strong diphtheria toxin-neutralising antibody response.

  17. Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines

    NASA Astrophysics Data System (ADS)

    Payne, Richard; McDonald, David; Byrne, Scott

    2015-10-01

    Due to changes in glycosyltransferase expression during tumorigenesis, the glycoproteins of cancer cells often carry highly truncated carbohydrate chains compared to those on healthy cells. These glycans are known as tumor-associated carbohydrate antigens, and are prime targets for use in vaccines for the prevention and treatment of cancer. Herein, we review the state-of-the-art in targeting the immune system towards tumor-associated glycopeptide antigens via synthetic self adjuvanting vaccines, in which the antigenic and adjuvanting moieties of the vaccines are present in the same molecule. The majority of the self-adjuvanting glycopeptide cancer vaccines reported to date employ antigens from mucin 1, a protein which is highly over-expressed and aberrantly glycosylated in many forms of cancer. The adjuvants used in these vaccines predominantly include lipopeptide- or lipoamino acid-based TLR2 agonists, although studies investigating stimulation of TLR9 and TLR4 are also discussed. Most of these adjuvants are highly lipophilic, and, upon conjugation to antigenic peptides, provide amphiphilic vaccine molecules. The amphiphilic nature of these vaccine constructs can lead to the formation of higher-order structures by vaccines in solution, which are likely to be important for their efficacy in vivo.

  18. Beyond antigens and adjuvants: formulating future vaccines.

    PubMed

    Moyer, Tyson J; Zmolek, Andrew C; Irvine, Darrell J

    2016-03-01

    The need to optimize vaccine potency while minimizing toxicity in healthy recipients has motivated studies of the formulation of vaccines to control how, when, and where antigens and adjuvants encounter immune cells and other cells/tissues following administration. An effective subunit vaccine must traffic to lymph nodes (LNs), activate both the innate and adaptive arms of the immune system, and persist for a sufficient time to promote a mature immune response. Here, we review approaches to tailor these three aspects of vaccine function through optimized formulations. Traditional vaccine adjuvants activate innate immune cells, promote cell-mediated transport of antigen to lymphoid tissues, and promote antigen retention in LNs. Recent studies using nanoparticles and other lymphatic-targeting strategies suggest that direct targeting of antigens and adjuvant compounds to LNs can also enhance vaccine potency without sacrificing safety. The use of formulations to regulate biodistribution and promote antigen and inflammatory cue co-uptake in immune cells may be important for next-generation molecular adjuvants. Finally, strategies to program vaccine kinetics through novel formulation and delivery strategies provide another means to enhance immune responses independent of the choice of adjuvant. These technologies offer the prospect of enhanced efficacy while maintaining high safety profiles necessary for successful vaccines.

  19. (Neo)adjuvant systemic therapy for melanoma.

    PubMed

    van Zeijl, M C T; van den Eertwegh, A J; Haanen, J B; Wouters, M W J M

    2017-03-01

    Surgery still is the cornerstone of treatment for patients with stage II and III melanoma, but despite great efforts to gain or preserve locoregional control with excision of the primary tumour, satellites, intransits, sentinel node biopsy and lymphadenectomy, surgery alone does not seem to improve survival any further. Prognosis for patients with high risk melanoma remains poor with 5-year survival rates of 40 to 80%. Only interferon-2b has been approved as adjuvant therapy since 1995, but clinical integration is low considering the high risk-benefit ratio. In recent years systemic targeted- and immunotherapy have proven to be beneficial in advanced melanoma and could be a promising strategy for (neo)adjuvant treatment of patients with resectable high risk melanomas as well. Randomised, placebo- controlled phase III trials on adjuvant systemic targeted- and immunotherapy are currently being performed using new agents like ipilimumab, pembrolizumab, nivolumab, vemurafenib and dabrafenib plus trametinib. In this article we review the literature on currently known adjuvant therapies and currently ongoing trials of (neo)adjuvant therapies in high risk melanomas.

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

    PubMed

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

    2015-01-23

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

  1. Montanide ISA 71 VG is Advantageous to Freund's Adjuvant in Immunization Against S. aureus Infection of Mice.

    PubMed

    Klimka, A; Michels, L; Glowalla, E; Tosetti, B; Krönke, M; Krut, O

    2015-05-01

    The enormous capacity of Staphylococcus aureus to acquire antibiotic resistance makes it a permanent task to search for and to develop new anti-infectives. One of the possible approaches is the early active immunization of risk patients and animal stocks to prevent S. aureus infections. Based on a S. aureus proteome screen with S. aureus-specific human antiserum, we have previously identified several anchorless cell wall proteins to be used as novel vaccine candidates. To develop an efficient anti-S. aureus vaccine, the supplemented adjuvants Montanide(™) ISA 71 VG and ISA 206 were compared to Freund's adjuvant in terms of handling, induction of cytokine profile, triggering antigen-specific immunoglobulin production of different IgG subclasses and provision of increased survival rates in our S. aureus sepsis mouse model. Immunization with ISA 71 VG in comparison with Freund's adjuvant induced slightly delayed but comparably strong increase of antigen-specific antibody titres and conferred protective effect against S. aureus challenge. In contrast using ISA 206 as adjuvant, significantly lower IgG titres and consequently, no protective effect against S. aureus infection were observed. Handling and tolerability of the Montanide is superior to Freund's adjuvant. Montanide(™) ISA 71 VG can serve as an effective adjuvant replacement for Freund's adjuvant in research with a prospective usage in animal and human vaccines against bacterial pathogens.

  2. 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.

  3. Nanopatch targeted delivery of both antigen and adjuvant to skin synergistically drives enhanced antibody responses.

    PubMed

    Fernando, Germain J P; Chen, Xianfeng; Primiero, Clare A; Yukiko, Sally R; Fairmaid, Emily J; Corbett, Holly J; Frazer, Ian H; Brown, Lorena E; Kendall, Mark A F

    2012-04-30

    Many vaccines make use of an adjuvant to achieve stronger immune responses. Alternatively, potent immune responses have also been generated by replacing the standard needle and syringe (which places vaccine into muscle) with devices that deliver vaccine antigen to the skin's abundant immune cell population. However it is not known if the co-delivery of antigen plus adjuvant directly to thousands of skin immune cells generates a synergistic improvement of immune responses. In this paper, we investigate this idea, by testing if Nanopatch delivery of vaccine - both the antigen and the adjuvant - enhances immunogenicity, compared to intramuscular injection. As a test-case, we selected a commercial influenza vaccine as the antigen (Fluvax 2008®) and the saponin Quil-A as the adjuvant. We found, after vaccinating mice, that anti-influenza IgG antibody and haemagglutinin inhibition assay titre response induced by the Nanopatch (with delivered dose of 6.5ng of vaccine and 1.4μg of Quil-A) were equivalent to that of the conventional intramuscular injection using needle and syringe (6000ng of vaccine injected without adjuvant). Furthermore, a similar level of antigen dose sparing (up to 900 fold) - with equivalent haemagglutinin inhibition assay titre responses - was also achieved by delivering both antigen and adjuvant (1.4μg of Quil-A) to skin (using Nanopatches) instead of muscle (intramuscular injection). Collectively, the unprecedented 900 fold antigen dose sparing demonstrates the synergistic improvement to vaccines by co-delivery of both antigen and adjuvant directly to skin immune cells. Successfully extending these findings to humans with a practical delivery device - like the Nanopatch - could have a huge impact on improving vaccines.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chickens were immunized subcutaneously with an Eimeria recombinant profilin protein plus ISA 70 VG (ISA 70) or ISA 71 VG (ISA 71) water-in-oil adjuvants, or with profilin alone, and comparative RNA microarray hybridizations were performed to ascertain global transcriptome changes induced by profilin...

  5. 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

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

    PubMed

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

    2014-05-01

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

  7. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer.

    PubMed

    Scheiermann, Julia; Klinman, Dennis M

    2014-11-12

    Synthetic oligonucleotides (ODN) that express unmethylated "CpG motifs" trigger cells that express Toll-like receptor 9. In humans this includes plasmacytoid dendritic cells and B cells. CpG ODN induce an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. Their utility as vaccine adjuvants was evaluated in a number of clinical trials. Results indicate that CpG ODN improve antigen presentation and the generation of vaccine-specific cellular and humoral responses. This work provides an up-to-date overview of the utility of CpG ODN as adjuvants for vaccines targeting infectious agents and cancer.

  8. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer

    PubMed Central

    Scheiermann, Julia; Klinman, Dennis M.

    2014-01-01

    Synthetic oligonucleotides (ODN) that express unmethylated “CpG motifs” trigger cells that express Toll-like receptor 9. In humans this includes plasmacytoid dendritic cells and B cells. CpG ODN induce an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. Their utility as vaccine adjuvants was evaluated in a number of clinical trials. Results indicate that CpG ODN improve antigen presentation and the generation of vaccine-specific cellular and humoral responses. This work provides an up-to-date overview of the utility of CpG ODN as adjuvants for vaccines targeting infectious agents and cancer. PMID:24975812

  9. Natural zeolite clinoptilolite: new adjuvant in anticancer therapy.

    PubMed

    Pavelić, K; Hadzija, M; Bedrica, L; Pavelić, J; Dikić, I; Katić, M; Kralj, M; Bosnar, M H; Kapitanović, S; Poljak-Blazi, M; Krizanac, S; Stojković, R; Jurin, M; Subotić, B; Colić, M

    2001-01-01

    Natural silicate materials, including zeolite clinoptilolite, have been shown to exhibit diverse biological activities and have been used successfully as a vaccine adjuvant and for the treatment of diarrhea. We report a novel use of finely ground clinoptilolite as a potential adjuvant in anticancer therapy. Clinoptilolite treatment of mice and dogs suffering from a variety of tumor types led to improvement in the overall health status, prolongation of life-span, and decrease in tumors size. Local application of clinoptilolite to skin cancers of dogs effectively reduced tumor formation and growth. In addition, toxicology studies on mice and rats demonstrated that the treatment does not have negative effects. In vitro tissue culture studies showed that finely ground clinoptilolite inhibits protein kinase B (c-Akt), induces expression of p21WAF1/CIP1 and p27KIP1 tumor suppressor proteins, and blocks cell growth in several cancer cell lines. These data indicate that clinoptilolite treatment might affect cancer growth by attenuating survival signals and inducing tumor suppressor genes in treated cells.

  10. Immunogenicity and protective efficacy of DMT liposome-adjuvanted tuberculosis subunit CTT3H vaccine.

    PubMed

    Teng, Xindong; Tian, Maopeng; Li, Jianrong; Tan, Songwei; Yuan, Xuefeng; Yu, Qi; Jing, Yukai; Zhang, Zhiping; Yue, Tingting; Zhou, Lei; Fan, Xionglin

    2015-01-01

    Different strategies have been proposed for the development of protein subunit vaccine candidates for tuberculosis (TB), which shows better safety than other types of candidates and the currently used Bacillus Calmette-Guérin (BCG) vaccine. In order to develop more effective protein subunits depending on the mechanism of cell-mediated immunity against TB, a polyprotein CTT3H, based on 5 immunodominant antigens (CFP10, TB10.4, TB8.4, Rv3615c, and HBHA) with CD8(+) epitopes of Mycobacterium tuberculosis, was constructed in this study. We vaccinated C57BL/6 mice with a TB subunit CTT3H protein in an adjuvant of dimethyldioctadecylammonium/monophosphoryl lipid A/trehalose 6,6'-dibehenate (DDA/MPL/TDB, DMT) liposome to investigate the immunogenicity and protective efficacy of this novel vaccine. Our results demonstrated that DMT liposome-adjuvanted CTT3H vaccine not only induced an antigen-specific CD4(+) Th1 response, but also raised the number of PPD- and CTT3H-specific IFN-γ(+) CD8(+) T cells and elicited strong CTL responses against TB10.4, which provided more effective protection against a 60 CFU M. tuberculosis aerosol challenge than PBS control and DMT adjuvant alone. Our findings indicate that DMT-liposome is an effective adjuvant to stimulate CD8(+) T cell responses and the DMT-adjuvanted subunit CTT3H vaccine is a promising candidate for the next generation of TB vaccine.

  11. Micro/nanoparticle adjuvants for antileishmanial vaccines: present and future trends.

    PubMed

    Badiee, Ali; Heravi Shargh, Vahid; Khamesipour, Ali; Jaafari, Mahmoud Reza

    2013-01-21

    Leishmania infection continues to have a major impact on public health inducing significant morbidity and mortality mostly in the poorest populations. Drug resistance, toxicity and side effects associated with expensive chemotherapeutic treatments and difficult reservoir control emphasize the need for a safe and effective vaccine which is not available yet. Although, Leishmanization (LZ) was shown to be effective against cutaneous leishmaniasis, standardization and safety are the main problems of LZ. First generation killed parasites demonstrated limited efficacy in phase 3 trials and moreover well defined molecules have not reached to phase 3 yet. Limited efficacy in vaccines against leishmaniasis is partly due to lack of an appropriate adjuvant. Hence, the use of particulate delivery systems as carriers for antigen and/or immunostimulatory adjuvants for effective delivery to the antigen-presenting cells (APCs) is a valuable strategy to enhance vaccine efficacies. Particle-based delivery systems such as emulsions, liposomes, virosomes, and polymeric microspheres have the potential for successfully delivering antigens, which can then be further improved via incorporation of additional antigenic or immustimulatory adjuvant components in or onto the particle carrier system. In this review, we have attempted to provide a list of particulate vaccine delivery systems involved in the production of candidate leishmaniasis vaccines and introduced some potentially useful vaccine delivery systems for leishmaniasis in future experiments. In conclusion, combination vaccines (adjuvant systems) composed of candidate antigens and more importantly well-developed particulate delivery systems, such as lipid-based particles containing immunostimulatory adjuvants, have a chance to succeed as antileishmanial vaccines.

  12. Pancreatic adenocarcinoma upregulated factor serves as adjuvant by activating dendritic cells through stimulation of TLR4

    PubMed Central

    Yang, Benjamin; Lee, Je-Jung; Lee, Hyun-Ju; Lee, Jaemin; Jung, In Duk; Han, Hee Dong; Lee, Seung-Hyun; Koh, Sang Seok; Wu, T.-C.; Park, Yeong-Min

    2015-01-01

    Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway. Furthermore, vaccination with PAUF treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice. Finally, we demonstrated that PAUF mediated DC activation and immune stimulation are dependent on TLR4. Our data provides evidence supporting PAUF as a promising adjuvant for DC based therapies, which can be applied in conjunction with other cancer therapies. Most importantly, our results serve as a reference for future investigation of human based adjuvants. PMID:26336989

  13. Microbiota Influences Vaccine and Mucosal Adjuvant Efficacy

    PubMed Central

    2017-01-01

    A symbiotic relationship between humans and the microbiota is critical for the maintenance of our health, including development of the immune system, enhancement of the epithelial barrier, and acquisition of nutrients. Recent research has shown that the microbiota impacts immune cell development and differentiation. These findings suggest that the microbiota may also influence adjuvant and vaccine efficacy. Indeed, several factors such as malnutrition and poor sanitation, which affect gut microbiota composition, impair the efficacy of vaccines. Although there is little evidence that microbiota alters vaccine efficacy, further understanding of human immune system-microbiota interactions may lead to the effective development of adjuvants and vaccines for the treatment of diseases. PMID:28261017

  14. Microbiota Influences Vaccine and Mucosal Adjuvant Efficacy.

    PubMed

    Kim, Yun-Gi

    2017-02-01

    A symbiotic relationship between humans and the microbiota is critical for the maintenance of our health, including development of the immune system, enhancement of the epithelial barrier, and acquisition of nutrients. Recent research has shown that the microbiota impacts immune cell development and differentiation. These findings suggest that the microbiota may also influence adjuvant and vaccine efficacy. Indeed, several factors such as malnutrition and poor sanitation, which affect gut microbiota composition, impair the efficacy of vaccines. Although there is little evidence that microbiota alters vaccine efficacy, further understanding of human immune system-microbiota interactions may lead to the effective development of adjuvants and vaccines for the treatment of diseases.

  15. Adjuvants and vector systems for allergy vaccines.

    PubMed

    Moingeon, Philippe; Lombardi, Vincent; Saint-Lu, Nathalie; Tourdot, Sophie; Bodo, Véronique; Mascarell, Laurent

    2011-05-01

    Allergen-specific immunotherapy represents a curative treatment of type I allergies. Subcutaneous immunotherapy is conducted with allergens adsorbed on aluminum hydroxide or calcium phosphate particles, whereas sublingual immunotherapy relies on high doses of soluble allergen without any immunopotentiator. There is a potential benefit of adjuvants enhancing regulatory and Th1 CD4+T cell responses during specific immunotherapy. Molecules affecting dendritic cells favor the induction of T regulatory cell and Th1 responses and represent valid candidate adjuvants for allergy vaccines. Furthermore, the interest in viruslike particles and mucoadhesive particulate vector systems, which may better address the allergen(s) to tolerogenic antigen-presenting cells, is documented.

  16. Improvement influenza HA2 DNA vaccine cellular and humoral immune responses with Mx bio adjuvant.

    PubMed

    Soleimani, Sina; Shahsavandi, Shahla; Maddadgar, Omid

    2017-03-01

    Immunization with DNA vaccines as a novel alternative to conventional vaccination strategy requires adjuvant for improving vaccine efficacy. The conserved immunogenic HA2 subunit, which harbors neutralizing epitopes is a promising vaccine candidate against influenza viruses. In this study, for the first time we explore the idea of using host interferon inducible Mx protein to increase the immunogenicity of HA2 H9N2 influenza DNA vaccine. The potency and safety of the Mx adjuvanted-HA2 vaccine was evaluated in BALB/c mice by different prime-boost strategies. To assess the effect of the vaccination on the virus clearance rate, mice were challenged with homologous influenza virus. Administration of the adjuvanted vaccine and boosting with the same regimen could effectively enhance both humoral and cellular immune responses in treated mice. These data demonstrated that Mx as host defense peptide can be potentiated for improving influenza vaccine efficacy.

  17. [Immunological adjuvants. Determinant factors in the efficacy-toxicity ratio of the contemporary vaccines].

    PubMed

    Batista-Duharte, Alexander; Lastre, Miriam; Pérez, Oliver

    2014-02-01

    To achieve effective and safe vaccines for the prevention of not yet controlled or re-emergent infectious diseases, one of the more importance aspects is to have immunological adjuvants that allow inducing a protective immune response with an appropriate safety profile. Since 1926 the aluminium compounds have been used as adjuvants for human vaccines, and only in the last 10 years have some new products been registered. Although there an enormous quantity of proposed candidates, the toxicity is the main factor that has limited their introduction into the clinic. In this work the mechanism of action are updated, and the toxicity of the immunological adjuvants are revised, especially those that have obtained clinical approval or are close to getting it.

  18. The effect of different adjuvants on immune parameters and protection following vaccination of sheep with a larval-specific antigen of the gastrointestinal nematode, Haemonchus contortus.

    PubMed

    Piedrafita, David; Preston, Sarah; Kemp, Joanna; de Veer, Michael; Sherrard, Jayne; Kraska, Troy; Elhay, Martin; Meeusen, Els

    2013-01-01

    It has recently been recognised that vaccine adjuvants play a critical role in directing the nature of a vaccine induced effector response. In the present study, several adjuvants were evaluated for their ability to protect sheep after field vaccination with the larval-specific Haemonchus contortus antigen, HcsL3. Using a suboptimal antigen dose, aluminium adjuvant was shown to reduce the cumulative faecal egg counts (cFEC) and worm burden by 23% and 25% respectively, in agreement with a previous study. The addition of Quil A to the aluminium-adjuvanted vaccine brought cFEC back to control levels. Vaccination with the adjuvant DEAE-dextran almost doubled the protection compared to the aluminium-adjuvanted vaccine resulting in 40% and 41% reduction in cFEC and worm counts compared to controls. Examination of skin responses following i.d. injection of exsheathed L3, revealed that cFEC was negatively correlated with wheal size and tissue eosinophils for the DEAE-dextran and aluminium-adjuvanted groups respectively. These studies have for the first time shown the potential of DEAE-dextran adjuvant for helminth vaccines, and discovered significant cellular correlates of vaccine-induced protection.

  19. Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin

    PubMed Central

    Kim, Donghyun; Kim, Yun-Gi; Seo, Sang-Uk; Kim, Dong-Jae; Kamada, Nobuhiko; Prescott, Dave; Philpott, Dana J.; Rosenstiel, Philip; Inohara, Naohiro; Núñez, Gabriel

    2016-01-01

    Cholera toxin (CT) is a potent adjuvant for inducing mucosal immune responses. However, the mechanism by which CT induces adjuvant activity remains unclear. Here we show that the microbiota is critical for inducing antigen-specific IgG production after intranasal immunization. After mucosal vaccination with CT, both antibiotic-treated mice and germ-free (GF) had reduced antigen-specific IgG, recall-stimulated cytokine responses, an impaired follicular helper T (TFH) response and reduced plasma cells. Recognition of symbiotic bacteria via Nod2 in CD11c+ cells was required for the adjuvanticity of CT. Reconstitution of GF mice with a Nod2 agonist or Staphylococcus sciuri having high Nod2-stimulatory activity was sufficient to promote robust CT adjuvant activity whereas bacteria with low Nod2-stimulatory activity did not. Mechanistically, CT enhanced Nod2-mediated cytokine production in DCs via intracellular cAMP. These results show an important role for the microbiota and the intracellular receptor Nod2 in promoting the mucosal adjuvant activity of CT. PMID:27064448

  20. Aluminum hydroxide nanoparticles show a stronger vaccine adjuvant activity than traditional aluminum hydroxide microparticles.

    PubMed

    Li, Xinran; Aldayel, Abdulaziz M; Cui, Zhengrong

    2014-01-10

    Aluminum hydroxide is used as a vaccine adjuvant in various human vaccines. Unfortunately, despite its favorable safety profile, aluminum hydroxide can only weakly or moderately potentiate antigen-specific antibody responses. When dispersed in an aqueous solution, aluminum hydroxide forms particulates of 1-20μm. There is increasing evidence that nanoparticles around or less than 200nm as vaccine or antigen carriers have a more potent adjuvant activity than large microparticles. In the present study, we synthesized aluminum hydroxide nanoparticles of 112nm. Using ovalbumin and Bacillus anthracis protective antigen protein as model antigens, we showed that protein antigens adsorbed on the aluminum hydroxide nanoparticles induced a stronger antigen-specific antibody response than the same protein antigens adsorbed on the traditional aluminum hydroxide microparticles of around 9.3μm. The potent adjuvant activity of the aluminum hydroxide nanoparticles was likely related to their ability to more effectively facilitate the uptake of the antigens adsorbed on them by antigen-presenting cells. Finally, the local inflammation induced by aluminum hydroxide nanoparticles in the injection sites was milder than that induced by microparticles. Simply reducing the particle size of the traditional aluminum hydroxide adjuvant into nanometers represents a novel and effective approach to improve its adjuvanticity.

  1. Non-invasive dual fluorescence in vivo imaging for detection of macrophage infiltration and matrix metalloproteinase (MMP) activity in inflammatory arthritic joints.

    PubMed

    Cho, Hongsik; Bhatti, Fazal-Ur-Rehman; Yoon, Tae Won; Hasty, Karen A; Stuart, John M; Yi, Ae-Kyung

    2016-05-01

    Detection and intervention at an early stage is a critical factor to impede arthritis progress. Here we present a non-invasive method to detect inflammatory changes in joints of arthritic mice. Inflammation was monitored by dual fluorescence optical imaging for near-infrared fluorescent (750F) matrix-metalloproteinase activatable agent and allophycocyanin-conjugated anti-mouse CD11b. Increased intensity of allophycocyanin (indication of macrophage accumulation) and 750F (indication of matrix-metalloproteinase activity) showed a biological relationship with the arthritis severity score and the histopathology score of arthritic joints. Our results demonstrate that this method can be used to detect early stages of arthritis with minimum intervention in small animal models.

  2. Lactic acid bacteria as adjuvants for sublingual allergy vaccines.

    PubMed

    Van Overtvelt, Laurence; Moussu, Helene; Horiot, Stéphane; Samson, Sandrine; Lombardi, Vincent; Mascarell, Laurent; van de Moer, Ariane; Bourdet-Sicard, Raphaëlle; Moingeon, Philippe

    2010-04-09

    We compared immunomodulatory properties of 11 strains of lactic acid bacteria as well as their capacity to enhance sublingual immunotherapy efficacy in a murine asthma model. Two types of bacterial strains were identified, including: (i) potent inducers of IL-12p70 and IL-10 in dendritic cells, supporting IFN-gamma and IL-10 production in CD4+ T cells such as Lactobacillus helveticus; (ii) pure Th1 inducers such as L. casei. Sublingual administration in ovalbumin-sensitized mice of L. helveticus, but not L. casei, reduced airways hyperresponsiveness, bronchial inflammation and proliferation of specific T cells in cervical lymph nodes. Thus, probiotics acting as a Th1/possibly Treg, but not Th1 adjuvant, potentiate tolerance induction via the sublingual route.

  3. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 182.99 Section....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior...

  4. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 182.99 Section....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior...

  5. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  6. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Adjuvants for pesticide chemicals. 182.99 Section....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  7. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  8. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 182.99 Section....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  9. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  10. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  11. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 582.99 Section... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior...

  12. Gaps in knowledge and prospects for research of adjuvanted vaccines.

    PubMed

    Seder, Robert; Reed, Steven G; O'Hagan, Derek; Malyala, Padma; D'Oro, Ugo; Laera, Donatello; Abrignani, Sergio; Cerundolo, Vincenzo; Steinman, Lawrence; Bertholet, Sylvie

    2015-06-08

    A panel of researchers working in different areas of adjuvanted vaccines deliberated over the topic, "Gaps in knowledge and prospects for research of adjuvanted vaccines" at, "Enhancing Vaccine Immunity and Value" conference held in July 2014. Several vaccine challenges and applications for new adjuvant technologies were discussed.

  13. Adjuvanted rush immunotherapy using CpG oligodeoxynucleotides in experimental feline allergic asthma.

    PubMed

    Reinero, Carol R; Cohn, Leah A; Delgado, Cherlene; Spinka, Christine M; Schooley, Elizabeth K; DeClue, Amy E

    2008-02-15

    Allergic asthma is driven by relative overexpression of Th2 cell-derived cytokines in response to aeroallergens. In independent studies, both allergen-specific rush immunotherapy (RIT) and CpG oligodeoxynucleotides (ODN) showed promise in blunting eosinophilic inflammation in a model of feline allergic asthma. We hypothesized that RIT using allergen and CpG ODN would work synergistically to dampen the asthmatic phenotype in experimentally asthmatic cats. Twelve cats with asthma induced using Bermuda grass allergen (BGA) were studied. Of these, six were administered adjuvanted BGA RIT using CpG ODN #2142; six were administered placebo (saline) RIT and later crossed over to adjuvanted RIT. Over 2 days, subcutaneous CpG ODN (0.5ng/kg) with BGA (increasing doses every 2h from 20 to 200microg) was administered. Adverse events were recorded and compared with historical controls. Percentage of eosinophils in bronchoalveolar lavage fluid (BALF), % peripheral CD4+CD25+ T regulatory cells (Tregs), lymphocyte proliferation in response to ConA, and cytokine concentrations in BALF were measured over 2 months. Group mean BALF % eosinophils for the adjuvanted RIT cats were significantly lower at week 1 and month 1 (p=0.03 for both), and marginally significantly lower at month 2 (p=0.09) compared with placebo RIT cats. By the end of the study, 8/12 treated cats had BALF % eosinophils within the reference range for healthy cats. Adjuvanted RIT, but not placebo RIT, cats had significant decreases in the ConA stimulation index over time (p=0.05). BALF IL-4 concentrations were significantly higher at week 1 in adjuvanted RIT cats compared with baseline and month 2, and also with placebo RIT cats at week 1. No significant differences were detected between treatments or over time for IL-10 or IFN-gamma concentrations in BALF or for %Tregs cells in peripheral blood. Adjuvanted RIT using CpG ODN in experimental feline asthma dampens eosinophilic airway inflammation. Adverse effects

  14. Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

    SciTech Connect

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

    2011-08-01

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

  15. In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice.

    PubMed

    Bouta, Echoe M; Wood, Ronald W; Brown, Edward B; Rahimi, Homaira; Ritchlin, Christopher T; Schwarz, Edward M

    2014-03-15

    Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with episodic flares. In TNF-Tg mice, a model of inflammatory-erosive arthritis, the popliteal lymph node (PLN) enlarges during the pre-arthritic 'expanding' phase, and then 'collapses' with adjacent knee flare associated with the loss of the intrinsic lymphatic pulse. As the mechanisms responsible are unknown, we developed in vivo methods to quantify lymph viscosity and pressure in mice with wild-type (WT), expanding and collapsed PLN. While no differences in viscosity were detected via multiphoton fluorescence recovery after photobleaching (MP-FRAP) of injected FITC-BSA, a 32.6% decrease in lymph speed was observed in vessels afferent to collapsed PLN (P < 0.05). Direct measurement of intra-lymph node pressure (LNP) demonstrated a decrease in expanding PLN versus WT pressure (3.41 ± 0.43 vs. 6.86 ± 0.56 cmH2O; P < 0.01), which dramatically increased to 9.92 ± 1.79 cmH2O in collapsed PLN. Lymphatic pumping pressure (LPP), measured indirectly by slowly releasing a pressurized cuff occluding indocyanine green (ICG), demonstrated an increase in vessels afferent to expanding PLN versus WT (18.76 ± 2.34 vs. 11.04 ± 1.47 cmH2O; P < 0.01), which dropped to 2.61 ± 0.72 cmH2O (P < 0.001) after PLN collapse. Herein, we document the first in vivo measurements of murine lymph viscosity and lymphatic pressure, and provide evidence to support the hypothesis that lymphangiogenesis and lymphatic transport are compensatory mechanisms to prevent synovitis via increased drainage of inflamed joints. Furthermore, the decrease in lymphatic flow and loss of LPP during PLN collapse are consistent with decreased drainage from the joint during arthritic flare, and validate these biomarkers of RA progression and possibly other chronic inflammatory conditions.

  16. 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

  17. Recurrent Pericarditis, an Unexpected Effect of Adjuvant Interferon Chemotherapy for Malignant Melanoma

    PubMed Central

    Marmoush, Fady; Shafi, Muhammad Ismail; Shah, Ashish

    2016-01-01

    Drug-induced pericarditis is a well-described cardiac pathology that can result from a variety of medications; however, interferon-mediated pericarditis is extremely rare. We present a case of a young female with recurrent pericarditis due to interferon therapy. The role of interferon in adjuvant chemotherapy is well known and yields good effect, but this case highlights the very uncommon phenomena of interferon induced pericarditis and the significant distress it can cause. PMID:27418981

  18. Suppression of collagen induced arthritis by idiotype coupled lymphoid cells

    SciTech Connect

    Nagler-Anderson, C.; Gurish, M.F.; Robinson, M.E.; Thorbecke, G.J.

    1986-03-01

    Studies were initiated to evaluate the regulatory influence of idiotype (Id) networks in an experimental auto-immune disease. Collagen induced arthritis is an animal model of polyarthritis induced in susceptible mice by immunization with collagen II (CII). A humoral immune response to CII appears to be critical for the development of diseases. If subpopulations of the anti-CII abs, important for the induction of arthritis, could be identified and manipulated through the presence of a major Id, it should be possible to decrease arthritis incidence by suppressing the production of these Ids. Specifically purified anti-CII abs from arthritic DBA/1 mice were coupled to syngeneic spleen cells and administered IV prior to intradermal immunization with CII. By day 34 after 1/sup 0/ immunization, 100% of control mice and 50% of treated mice had developed arthritis. Suppression of the Id population administered to the treated group was confirmed by RIA. Sera from individual mice were tested as inhibitors of binding of /sup 125/I-labelled polyclonal DBA/1 anti-CII to a rabbit anti-Id directed against polyclonal anti-CII isolated from the sera of arthritic mice. Mean percentage of inhibition of binding of /sup 125/I-Id to rabbit anti-Id by sera from non-arthritic treated mice was found to be significantly lower than that observed in the arthritic control group (p = .045), but did not correlate with total anti-CII ab titers.

  19. Mucosal and systemic adjuvant activity of alphavirus replicon particles

    NASA Astrophysics Data System (ADS)

    Thompson, Joseph M.; Whitmore, Alan C.; Konopka, Jennifer L.; Collier, Martha L.; Richmond, Erin M. B.; Davis, Nancy L.; Staats, Herman F.; Johnston, Robert E.

    2006-03-01

    Vaccination represents the most effective control measure in the fight against infectious diseases. Local mucosal immune responses are critical for protection from, and resolution of, infection by numerous mucosal pathogens. Antigen processing across mucosal surfaces is the natural route by which mucosal immunity is generated, as peripheral antigen delivery typically fails to induce mucosal immune responses. However, we demonstrate in this article that mucosal immune responses are evident at multiple mucosal surfaces after parenteral delivery of Venezuelan equine encephalitis virus replicon particles (VRP). Moreover, coinoculation of null VRP (not expressing any transgene) with inactivated influenza virions, or ovalbumin, resulted in a significant increase in antigen-specific systemic IgG and fecal IgA antibodies, compared with antigen alone. Pretreatment of VRP with UV light largely abrogated this adjuvant effect. These results demonstrate that alphavirus replicon particles possess intrinsic systemic and mucosal adjuvant activity and suggest that VRP RNA replication is the trigger for this activity. We feel that these observations and the continued experimentation they stimulate will ultimately define the specific components of an alternative pathway for the induction of mucosal immunity, and if the activity is evident in humans, will enable new possibilities for safe and inexpensive subunit and inactivated vaccines. vaccine vector | Venezuelan equine encephalitis virus | viral immunology | RNA virus

  20. Ethoxylated adjuvants of glyphosate-based herbicides are active principles of human cell toxicity.

    PubMed

    Mesnage, R; Bernay, B; Séralini, G-E

    2013-11-16

    Pesticides are always used in formulations as mixtures of an active principle with adjuvants. Glyphosate, the active ingredient of the major pesticide in the world, is an herbicide supposed to be specific on plant metabolism. Its adjuvants are generally considered as inert diluents. Since side effects for all these compounds have been claimed, we studied potential active principles for toxicity on human cells for 9 glyphosate-based formulations. For this we detailed their compositions and toxicities, and as controls we used a major adjuvant (the polyethoxylated tallowamine POE-15), glyphosate alone, and a total formulation without glyphosate. This was performed after 24h exposures on hepatic (HepG2), embryonic (HEK293) and placental (JEG3) cell lines. We measured mitochondrial activities, membrane degradations, and caspases 3/7 activities. The compositions in adjuvants were analyzed by mass spectrometry. Here we demonstrate that all formulations are more toxic than glyphosate, and we separated experimentally three groups of formulations differentially toxic according to their concentrations in ethoxylated adjuvants. Among them, POE-15 clearly appears to be the most toxic principle against human cells, even if others are not excluded. It begins to be active with negative dose-dependent effects on cellular respiration and membrane integrity between 1 and 3ppm, at environmental/occupational doses. We demonstrate in addition that POE-15 induces necrosis when its first micellization process occurs, by contrast to glyphosate which is known to promote endocrine disrupting effects after entering cells. Altogether, these results challenge the establishment of guidance values such as the acceptable daily intake of glyphosate, when these are mostly based on a long term in vivo test of glyphosate alone. Since pesticides are always used with adjuvants that could change their toxicity, the necessity to assess their whole formulations as mixtures becomes obvious. This challenges

  1. Protoporphyrin IX distribution after intra-articular and systemic application of 5-aminolevulinic acid in healthy and arthritic joints

    NASA Astrophysics Data System (ADS)

    Huettmann, Gereon; Hendrich, Christian; Birngruber, Reginald; Lehnert, Christiane; Seara, Jose; Siebert, Werner E.; Diddens, Heyke C.

    1996-04-01

    Arthroscopic synovectomy, which is limited today to the large joints, is an important early treatment of rheumatoid arthritis (RA). Photodynamic therapy (PDT) is potentially to be a less invasive method of removing the synovial membrane. Therefore, in a rabbit model of RA, the accumulation of the photosensitizer Protoporphyrin IX (PPIX) after intra-articular and systemic application of ALA into arthritic rabbit knee joints was studied in skin, patella, synovial tissue, and meniscus by fluorescence microscopy. PPIX fluorescence was measured in biopsies taken at different times after application of neutral and acid ALA solutions. Significant PPIX fluorescence was observed in the synovial membrane and skin 2 and 4 hours after application. Using intra-articular application, ALA solutions prepared with pH 5.5 were at least as efficient as neutral solutions in sensitizing the synovial membrane. Skin also showed PPIX within 4 hours after application. After 24 hours, a marginal PPIX fluorescence was detected in these tissues. On the other hand, in cartilage and meniscus significant PPIX accumulation was still observed 24 hours after ALA injection. Systemic application of ALA also showed a good accumulation of PPIX. Further experiments are needed to show whether accumulation of the photosensitizer and tissue selectivity are sufficient for a successful treatment of rheumatoid synovitis.

  2. Layer-by-layer assembled magnetic prednisolone microcapsules (MPC) for controlled and targeted drug release at rheumatoid arthritic joints

    NASA Astrophysics Data System (ADS)

    Prabu, Chakkarapani; Latha, Subbiah; Selvamani, Palanisamy; Ahrentorp, Fredrik; Johansson, Christer; Takeda, Ryoji; Takemura, Yasushi; Ota, Satoshi

    2017-04-01

    We report here in about the formulation and evaluation of Magnetic Prednisolone Microcapsules (MPC) developed in order to improve the therapeutic efficacy relatively at a low dose than the conventional dosage formulations by means of magnetic drug targeting and thus enhancing bioavailability at the arthritic joints. Prednisolone was loaded to poly (sodium 4-styrenesulfonate) (PSS) doped calcium carbonate microspheres confirmed by the decrease in surface area from 97.48 m2/g to 12.05 of m2/g by BET analysis. Adsorption with oppositely charged polyelectrolytes incorporated with iron oxide nanoparticles was confirmed through zeta analysis. Removal of calcium carbonate core yielded MPC with particle size of 3.48 μm, zeta potential of +29.7 mV was evaluated for its magnetic properties. Functional integrity of MPC was confirmed through FT-IR spectrum. Stability studies were performed at 25 °C±65% relative humidity for 60 days showed no considerable changes. Further the encapsulation efficiency of 63%, loading capacity of 18.2% and drug release of 88.3% for 36 h and its kinetics were also reported. The observed results justify the suitability of MPC for possible applications in the magnetic drug targeting for efficient therapy of rheumatoid arthritis.

  3. Simultaneous dual frequency 1H and 19F open coil imaging of arthritic rabbit knee at 3T.

    PubMed

    Hockett, Franklin D; Wallace, Kirk D; Schmieder, Anne H; Caruthers, Shelton D; Pham, Christine T N; Wickline, Samuel A; Lanza, Gregory M

    2011-01-01

    The combination of sensitive magnetic resonance techniques with a selective site-targeted nanoparticle contrast agent has a demonstrated utility for molecular imaging studies. By detecting a unique signature of the contrast agent, this approach can be employed to identify specific bio-molecular markers and observe cellular-level processes within a large and complex organism (e.g., in vivo rabbit). The objective of the present investigation was to design, fabricate and characterize a radio-frequency (RF) coil for the dual frequency ((1)H and (19)F) simultaneous collection of both nuclei images in a 3T field, in order to facilitate studies of arthritic knee degradation in rabbits. The coil supports both transmit and receive modes. The supporting activities included: 1) establishing a technical database for calculating the required coil parameters, 2) selection of a favorable coil geometry, and 3) adaption of existing RF measurement techniques to the design, development and electrical evaluation of the coil. The coil is used in conjunction with a Philips Medical Systems clinical MRI scanner, requiring all RF simultaneous dual frequency ((1)H and (19)F) coils to operate in both transmit and receive modes. A commercial version of SPICE (simulation program with integrated circuit emphasis) was used to estimate significant operational parameters prior to fabricating the imaging coil. Excellent images were obtained with the fabricated coil and no operational problems were observed that would limit the use of other coil geometries and field strengths.

  4. New generation adjuvants--from empiricism to rational design.

    PubMed

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-08

    Adjuvants are an essential component of modern vaccine development. Despite many decades of development, only a few types of adjuvants are currently included in vaccines approved for human use. In order to better understand the reasons that development of some adjuvants succeeded while many others failed, we discuss some of the common attributes of successful first generation adjuvants. Next, we evaluate current trends in the development of second generation adjuvants, including the potential advantages of rationally designed synthetic immune potentiators appropriately formulated. Finally, we discuss desirable attributes of next generation adjuvants. Throughout, we emphasize that the importance of formulation and analytical characterization in all aspects of vaccine adjuvant development is often underappreciated. We highlight the formulation factors that must be evaluated in order to optimize interactions between vaccine antigens, immune potentiators, and particulate formulations, and the resulting effects on safety, biological activity, manufacturability, and stability.

  5. Biotechnology approaches to produce potent, self-adjuvanting antigen-adjuvant fusion protein subunit vaccines.

    PubMed

    Moyle, Peter Michael

    Traditional vaccination approaches (e.g. live attenuated or killed microorganisms) are among the most effective means to prevent the spread of infectious diseases. These approaches, nevertheless, have failed to yield successful vaccines against many important pathogens. To overcome this problem, methods have been developed to identify microbial components, against which protective immune responses can be elicited. Subunit antigens identified by these approaches enable the production of defined vaccines, with improved safety profiles. However, they are generally poorly immunogenic, necessitating their administration with potent immunostimulatory adjuvants. Since few safe and effective adjuvants are currently used in vaccines approved for human use, with those available displaying poor potency, or an inability to stimulate the types of immune responses required for vaccines against specific diseases (e.g. cytotoxic lymphocytes (CTLs) to treat cancers), the development of new vaccines will be aided by the availability of characterized platforms of new adjuvants, improving our capacity to rationally select adjuvants for different applications. One such approach, involves the addition of microbial components (pathogen-associated molecular patterns; PAMPs), that can stimulate strong immune responses, into subunit vaccine formulations. The conjugation of PAMPs to subunit antigens provides a means to greatly increase vaccine potency, by targeting immunostimulation and antigen to the same antigen presenting cell. Thus, methods that enable the efficient, and inexpensive production of antigen-adjuvant fusions represent an exciting mean to improve immunity towards subunit antigens. Herein we review four protein-based adjuvants (flagellin, bacterial lipoproteins, the extra domain A of fibronectin (EDA), and heat shock proteins (Hsps)), which can be genetically fused to antigens to enable recombinant production of antigen-adjuvant fusion proteins, with a focus on their

  6. [Adjuvant therapy of breast cancer with trastuzumab].

    PubMed

    Beneder, Christine; Marth, Christian

    2008-01-01

    With the approval of trastuzumab (Herceptin) in 1998, a new era of breast cancer treatment has been heralded. This antibody is directed at the intracellular domain of a member of the epidermal growth factor receptor family, the so-called HER2 receptor. About 25-30% of all breast cancers overexpress this factor, which is associated with a more unfavorable prognosis. Trastuzumab is indicated for patients whose tumor overexpresses HER2. All previous studies on the adjuvant therapy with trastuzumab show very consistent results and provide evidence that the risk of recurrence can be reduced by half by the antibody. Nevertheless, there are still numerous open and controversially discussed questions concerning the use of trastuzumab in adjuvant therapy.

  7. [Neoadjuvant or Adjuvant Chemotherapy for Bladder Cancer?].

    PubMed

    Hupe, M C; Kramer, M W; Kuczyk, M A; Merseburger, A S