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Prevention and Therapy of Hepatocellular Carcinoma by Vaccination with TM4SF5 Epitope-CpG-DNA-Liposome Complex without Carriers  [PDF]
Sanghoon Kwon, Dongbum Kim, Byoung Kwon Park, Sunhee Cho, Kwang Dong Kim, Young-Eun Kim, Cheung-Seog Park, Hyun-Jong Ahn, Jae-Nam Seo, Kyung-Chan Choi, Doo-Sik Kim, Younghee Lee, Hyung-Joo Kwon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033121
Abstract: Although peptide vaccines have been actively studied in various animal models, their efficacy in treatment is limited. To improve the efficacy of peptide vaccines, we previously formulated an efficacious peptide vaccine without carriers using the natural phosphodiester bond CpG-DNA and a special liposome complex (Lipoplex(O)). Here, we show that immunization of mice with a complex consisting of peptide and Lipoplex(O) without carriers significantly induces peptide-specific IgG2a production in a CD4+ cells- and Th1 differentiation-dependent manner. The transmembrane 4 superfamily member 5 protein (TM4SF5) has gained attention as a target for hepatocellular carcinoma (HCC) therapy because it induces uncontrolled growth of human HCC cells via the loss of contact inhibition. Monoclonal antibodies specific to an epitope of human TM4SF5 (hTM4SF5R2-3) can recognize native mouse TM4SF5 and induce functional effects on mouse cancer cells. Pre-immunization with a complex of the hTM4SF5R2-3 epitope and Lipoplex(O) had prophylactic effects against tumor formation by HCC cells implanted in an mouse tumor model. Furthermore, therapeutic effects were revealed regarding the growth of HCC when the vaccine was injected into mice after tumor formation. These results suggest that our improved peptide vaccine technology provides a novel prophylaxis measure as well as therapy for HCC patients with TM4SF5-positive tumors.
Immunization with a Hemagglutinin-Derived Synthetic Peptide Formulated with a CpG-DNA-Liposome Complex Induced Protection against Lethal Influenza Virus Infection in Mice  [PDF]
Jae Won Rhee,Dongbum Kim,Byung Kwon Park,Sanghoon Kwon,Sunhee Cho,Ilseob Lee,Man-Seong Park,Jae-Nam Seo,Yong-Sun Kim,Hong Seok Choi,Younghee Lee,Hyung-Joo Kwon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048750
Abstract: Whole-virus vaccines, including inactivated or live-attenuated influenza vaccines, have been conventionally developed and supported as a prophylaxis. These currently available virus-based influenza vaccines are widely used in the clinic, but the vaccine production takes a long time and a huge number of embryonated chicken eggs. To overcome the imperfection of egg-based influenza vaccines, epitope-based peptide vaccines have been studied as an alternative approach. Here, we formulated an efficacious peptide vaccine without carriers using phosphodiester CpG-DNA and a special liposome complex. Potential epitope peptides predicted from the hemagglutinin (HA) protein of the H5N1 A/Viet Nam/1203/2004 strain (NCBI database, AAW80717) were used to immunize mice along with phosphodiester CpG-DNA co-encapsulated in a phosphatidyl-β-oleoyl-γ-palmitoyl ethanolamine (DOPE):cholesterol hemisuccinate (CHEMS) complex (Lipoplex(O)) without carriers. We identified a B cell epitope peptide (hH5N1 HA233 epitope, 14 amino acids) that can potently induce epitope-specific antibodies. Furthermore, immunization with a complex of the B cell epitope and Lipoplex(O) completely protects mice challenged with a lethal dose of recombinant H5N1 virus. These results suggest that our improved peptide vaccine technology can be promptly applied to vaccine development against pandemic influenza. Furthermore our results suggest that potent epitopes, which cannot be easily found using proteins or a virus as an antigen, can be screened when we use a complex of peptide epitopes and Lipoplex(O).
Cholesterol-Peptide Hybrids to Form Liposome-Like Vesicles for Gene Delivery  [PDF]
Qiong Tang, Bin Cao, Haiyan Wu, Gang Cheng
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054460
Abstract: In this paper, four amphiphilic cholesterol-peptide conjugates (Ch-R5H5, Ch-R3H3, Ch-R5 and Ch-R5) were designed and synthesized, and their properties in gene delivery were evaluated in vitro with an aim of developing more efficient gene delivery carriers. These amphiphilic cholesterol-peptide conjugates are composed of hydrophobic cholesterol and positively charged peptides. They were able to self-assemble into micelles at low concentrations and their critical micelle concentrations in phosphate buffered saline (pH 7.4) are ≤85 μg/mL. Amphiphilic cholesterol-peptide conjugates condensed DNA more efficiently than a hydrophilic cationic oligoarginine (R10) peptide with no hydrophobic segment. Their transfection efficiencies were at least two orders of magnitude greater than that of R10 peptide in HEK-293 cells. Moreover, the introduction of histidine residues in cholesterol-peptide conjugates led to higher gene expression efficiency compared with cholesterol-peptides without histidine (Ch-R5 and Ch-R3), and the luciferase expression level was comparable or even higher than that induced by PEI at its optimal N/P ratio. In particular, Ch-R5H5 condensed DNA into smaller nanoparticles than Ch-R3H3 at higher N/P ratios, and the minimum size of Ch-R5H5/DNA complexes was 180 nm with zeta potential of 23 mV, achieved at the N/P ratio of 30. This liposome-like vesicle may be a promising gene delivery carrier for intravenous therapy.
Evaluation of the immunogenicity of liposome encapsulated HVR1 and NS3 regions of genotype 3 HCV, either singly or in combination
Gouri M Gupte, Vidya A Arankalle
Virology Journal , 2012, DOI: 10.1186/1743-422x-9-74
Abstract: HCV RNA extracted from serum samples of 49 chronically infected patients was PCR amplified to obtain HVR1 region. These amplified products were cloned to obtain 20 clones per sample in order to identify the quasispecies pattern. The HVR1 consensus sequence, along with three variants was reverse transcribed to obtain peptides. The peptides were checked for immunoreactivity individually, as a pool or as a single peptide tetramer interspersed with four glycine residues. Anti-HCV positivity varied from 42.6% (tetramer) to 92.2% (variant-4) when 115 anti-HCV positive sera representing genotypes 1, 3, 4 and 6 were screened. All the 95 anti-HCV negatives were scored negative by all antigens. Mice were immunized with different liposome encapsulated or Al(OH)3 adjuvanted formulations of HVR1 variants and recombinant NS3 protein, and monitored for anti-HVR1 and anti-NS3 antibody titres, IgG isotypes and antigen specific cytokine levels. A balanced Th1/Th2 isotyping response with high antibody titres was observed in most of the liposome encapsulated antigen groups. The effect of liposomes and aluminium hydroxide on the expression of immune response genes was studied using Taqman Low Density Array. Both Th1 (IFN-gamma, Il18) and Th2 (Il4) genes were up regulated in the liposome encapsulated HVR1 variant pool-NS3 combination group. In-vitro binding of the virus to anti-HVR1 antibodies was demonstrated.The optimum immunogen was identified to be combination of peptides of HVR1 consensus sequence and its variants along with pNS3 encapsulated in liposomes, which could generate both cellular and humoral immune responses in mice deserving further evaluation in a suitable cell culture system/non-human primate model.Hepatitis C virus (HCV), a major causative agent of chronic hepatitis is distributed worldwide with an estimated 170 million carriers. HCV displays a high rate of mutation contributed by both host and viral components [1-4] and exists in infected patients as a quasispecies,
Antiphospholipid antibodies in Brazilian hepatitis C virus carriers
Atta, A.M.;Estevam, P.;Paraná, R.;Pereira, C.M.;Leite, B.C.O.;Sousa-Atta, M.L.B.;
Brazilian Journal of Medical and Biological Research , 2008, DOI: 10.1590/S0100-879X2008005000024
Abstract: hepatitis c, a worldwide viral infection, is an important health problem in brazil. the virus causes chronic infection, provoking b lymphocyte dysfunction, as represented by cryoglobulinemia, non-organ-specific autoantibody production, and non-hodgkin's lymphoma. the aim of this research was to screen for the presence of antiphospholipid autoantibodies in 109 brazilian hepatitis c virus carriers without clinical history of antiphospholipid syndrome. forty healthy individuals were used as the control group. iga, igg, and igm antibodies against cardiolipin and β2-glycoprotein i were measured with an enzyme-linked immunosorbent assay, using a cut-off point of either 20 upl or 20 sbu. while 24 (22.0%) hepatitis c carriers had moderate titers of igm anticardiolipin antibodies (median, 22.5 mpl; 95%ci: 21.5-25.4 mpl), only three carriers (<3%) had igg anticardiolipin antibodies (median, 23 gpl; 95%ci: 20.5-25.5 gpl). furthermore, iga anticardiolipin antibodies were not detected in these individuals. male gender and igm anticardiolipin seropositivity were associated in the hepatitis c group (p = 0.0004). iga anti-β2-glycoprotein-i antibodies were detected in 29 of 109 (27.0%) hepatitis c carriers (median, 41 sau; 95%ci: 52.7-103.9 sau). twenty patients (18.0%) had igm anti-β2-glycoprotein i antibodies (median, 27.6 smu; 95%ci: 23.3-70.3 smu), while two patients had igg antibodies against this protein (titers, 33 and 78 sgu). antiphospholipid antibodies were detected in only one healthy individual, who was seropositive for igm anticardiolipin. we concluded that brazilian individuals chronically infected with hepatitis c virus present a significant production of antiphospholipid antibodies, mainly iga anti-β2-glycoprotein i antibodies, which are not associated with clinical manifestations of antiphospholipid syndrome.
Immunostimulatory effects of three classes of CpG oligodeoxynucleotides on PBMC from HCV chronic carriers
Cooper Curtis L,Ahluwalia Navneet K,Efler Susan M,Vollmer J?rg
Journal of Immune Based Therapies and Vaccines , 2008, DOI: 10.1186/1476-8518-6-3
Abstract: Background Chronic hepatitis C virus (HCV) infection results from weak or absent T cell responses. Pegylated-interferon-alpha (IFN-α) and ribavirin, the standard of care for chronic HCV, have numerous immune effects but are not potent T cell activators. A potent immune activator such as TLR9 agonist CpG oligodeoxynucleotide (CpG) may complement current treatment approaches. Methods Peripheral blood mononuclear cells (PBMC) obtained from HCV chronic carriers who failed previous treatment and from healthy donors were incubated in vitro with the three main CpG classes (A, B or C), recombinant IFN-α-2b (IntronA) and/or ribavirin. Proliferation and cytokine secretion (IFN-α, IL-10 and IP-10) were evaluated. Results CpG induced proliferation and cytokine secretion in patterns expected for each CpG class with similar group means for HCV and healthy donors. IntronA and ribavirin, alone or together, had no detectable effects. IntronA and C-Class CpG together induced more IFN-α than CpG alone in most subjects. IFN-α secretion was proportional to the number of plasmacytoid dendritic cells in PBMC from healthy donors but not HCV donors in whom responses were highly heterogeneous. Conclusion The strong immune stimulatory effect of CpG on PBMC isolated from treatment-failed HCV patients suggests possible utility alone or in combination with current HCV antiviral treatment.
Immunogenicity of a Promiscuous T Cell Epitope Peptide Based Conjugate Vaccine against Benzo[a]pyrene: Redirecting Antibodies to the Hapten  [PDF]
Mario T. Schellenberger, Nathalie Grova, Sophie Farinelle, Stéphanie Willième, Dominique Revets, Claude P. Muller
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038329
Abstract: The prototype polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P) is an environmental pollutant and food contaminant of epidemiological importance. To protect against adverse effects of this ubiquitous carcinogen, we developed an immunoprophylactic strategy based on a B[a]P-protein conjugate vaccine to induce B[a]P specific antibodies (Grova et al., Vaccine. 2009;27:4142–51). Here, we investigated in mice the efficacy of B[a]P-peptide conjugates based on promiscuous T cell epitopes (TCE) into further improve this approach. We showed that B[a]P-peptide conjugates induced very different levels of hapten-specific antibodies with variable functional efficacy, depending on the carrier. In some cases peptide carriers induced a more efficient antibody response against B[a]P than tetanus toxoid as a protein carrier, with the capacity to sequester more B[a]P in the blood. Reducing the carrier size to a single TCE can dramatically shift the antibody bias from the carrier to the B[a]P. Conjugates based on the TCE FIGITEL induced the best anti-hapten response and no antibodies against the carrier peptide. Some peptide conjugates increased the selectivity of the antibodies for the activated metabolite 7,8-diol-B[a]P and B[a]P by one or two orders of magnitude. The antibody efficacy was also demonstrated in their ability to sequester B[a]P in the blood and modulate its faecal excretion (15–56%). We further showed that pre-existing immunity to the carrier from which the TCE was derived did not reduce the immunogenicity of the peptide conjugate. In conclusion, we showed that a vaccination against B[a]P using promiscuous TCEs of tetanus toxin as carriers is feasible even in case of a pre-existing immunity to the toxoid and that some TCE epitopes dramatically redirect the antibody response to the hapten. Further studies to demonstrate a long-term protection of an immunoprophylactic immunisation against B[a]P are warranted.
CpG oligodeoxynucleotide stimulates production of anti-neutrophil cytoplasmic antibodies in ANCA associated vasculitis
Plinio R Hurtado, Lisa Jeffs, Jodie Nitschke, Mittal Patel, Ghafar Sarvestani, John Cassidy, Pravin Hissaria, David Gillis, Chen Au Peh
BMC Immunology , 2008, DOI: 10.1186/1471-2172-9-34
Abstract: We have confirmed that unmethylated CpG oligonucleotide is a potent stimulator of antibody production by PBMC in vitro. The stimulation of PBMC with CpG oligonucleutides resulted in the production of similar amounts of IgG in both ANCA+ patients and normal controls. In spite of this, PR3 ANCA+ patients synthesised significantly higher amount of IgG ANCA than normal controls. In MPO ANCA+ patients, there was a tendency for patients to produce higher amount of ANCA than controls, however, the difference did not reach significance. Furthermore, we were able to detect circulating MPO-reactive B cells by ELISpot assay from the peripheral blood of 2 MPO+ ANCA vasculitis patients. Together, this indicates that circulating anti-neutrophil autoreactive B cells are present in ANCA+ vasculitis patients, and they are capable of producing antibodies in response to CpG stimulation. Of note, CpG also induced the production of the relevant autoantibodies in patients with other types of autoimmune diseases.Circulating ANCA autoreactive B cells are present in patients with ANCA+ vasculitis. The production of ANCA from these cells in response to unmethylated CpG stimulation lead us to propose that stimulation of these cells by immunostimulatory DNA sequences such as CpG oligodeoxynucleotide during infection may provide a link between infection and ANCA associated vasculitis. This phenomenon may also apply to other antibody mediated autoimmune diseases.The presence of circulating anti-neutrophil cytoplasmic antibodies (ANCA) has been found to be strongly associated with the development of Wegener's Granulomatosis and Microscopic Polyangiitis [1,2], commonly known as ANCA associated vasculitis. These conditions are characterised by systemic necrotising vasculitis, arthralgia, myalgia, inflammation of the upper and lower respiratory tracts, and acute necrotising glomerulonephritis. Proteinase-3 (PR3) and myeloperoxidase (MPO) are the most common neutrophil antigens targeted [3,4]. Notabl
A minimal model of peptide binding predicts ensemble properties of serum antibodies
Victor Greiff, Henning Redestig, Juliane Lück, Nicole Bruni, Atijeh Valai, Susanne Hartmann, Sebastian Rausch, Johannes Schuchhardt, Michal Or-Guil
BMC Genomics , 2012, DOI: 10.1186/1471-2164-13-79
Abstract: Multivariate regression analysis relating peptide sequence to measured signals led to the definition of amino acid-associated weights. Although these weights do not contain information on amino acid position, they predict up to 40-50% of the binding profiles' variation. Mathematical modeling shows that this position-independent ansatz is only adequate for highly diverse random antibody mixtures which are not dominated by a few antibodies. Experimental results suggest that sera from healthy individuals correspond to that case, in contrast to sera of infected ones.Our results indicate that position-independent amino acid-associated weights predict linear epitope binding of antibody mixtures only if the mixture is random, highly diverse, and contains no dominant antibodies. The discovered ensemble property is an important step towards an understanding of peptide-array serum-antibody binding profiles. It has implications for both serological diagnostics and B cell epitope mapping.The functional antibody repertoire (FABR), the set of all antibodies produced by plasma cells at any one time, determines the immune system's perception of the antigen universe. The FABR is shaped throughout the life of an individual by various stages and selection events during B cell development that take place in the fetal liver, in the bone marrow and in secondary lymphatic organs. As the FABR is subject to constant change due to continuous antigen encounter and establishment of immunological memory [1], it encompasses a variety of specificities and affinities for a wide range of antigens [2]. The FABR's investigation thus provides the possibility to gather information about both past and on-going immune responses, and ultimately about the immune state of the body [3].Since the FABR is highly diverse and the production of antibodies is a hallmark of many infectious and autoimmune diseases, high-throughput immunoblot and microarray technologies have been used intensively for large-scale prof
Relationship Between Cyclic Citrullinated Peptide Antibodies Positivity and HLA-DRB1 Shared Epitope Alleles in Patients with Rheumatoid Arthritis in Turkey
?dris Dayan,Canan T?k?z,Fatma Taneli,Cevval Ulman
Turkish Journal of Rheumatology , 2010,
Abstract: Objective: The most characteristic genetic risk factors for rheumatoid arthritis (RA), the HLA-DRB1 shared epitope (SE) alleles, encode for a common amino acid sequence in the peptide-presenting part of the HLA class II molecule. These SE alleles have been described recently to be a risk factor for the development of antibodies against citrullinated proteins in RA. The current study was performed to investigate the association between the cyclic citrullinated peptide antibodies (anti-CCP) and HLA-DR1 HLA-DRB1 shared epitope alleles in patients with RA in Turkey.Materials and Methods: Sixty patients with RA who were newly diagnosed or under conventional treatment in our clinic and 60 healthy volunteers as controls were enrolled in the study. In patients with RA anti-CCP levels were investigated with enzyme-linked immunosorbent assay and HLA-DRB1 subtyping and SE was assessed by polymerase chain reaction. Only anti-CCP was measured in healthy volunteers.Results: SE was positive in 50% of the patients with RA. Amongst the SE carriers, 30% of them were carrying double copy of SE. While anti-CCP was positive in 73,3% of patients with RA, this ratio was 0% in healthy volunteers. We determined that the existence of SE increases the positivity of anti-CCP (OR=4,3, 95% [CI], P=0.04 ), and a significant relationship was found between the anti-CCP positivity and the RF positivity. (OR=5,3, 95% [CI] P<0.05). Conclusion: The results of the present study revealed that Turkish patients with RA carrying SE with HLA-DRB1 genes is significantly related with the production of anti-CCP. The diagnostic sensitivity and specificity of anti-CCP for RA is determined as 73,3% and 100% respectively.
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