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At least 1,639 records · Page 91Linked to original sources
PubMed2005

Reduced cellular immune responses following immunization with a multi-gene HIV-1 vaccine.

We investigated the effects of immunizing with several genes and subtypes of HIV-1. The genes used as immunogens were: gp160 envelope (env subtypes A, B and C), p37gag (gag subtypes A and B), rev (subtype B) and reverse transcriptase (RT subtype B). The different genes are all carried by separate plasmids. C57BL/6 and BALB/c mice were immunized with different combinations of the genes together with recombinant cytokine granulocyte macrophage-colony stimulating factor. The env genes injected alone induced significantly stronger cellular responses to envelope in both strains of mice than when env genes were injected together with gag and RT genes. In the C57BL/6 mice, the envelope specific responses were significantly increased after spatial separation of env genes from gag and RT genes as compared to when all vaccine genes were injected as a mixture. The gag responses were strong in gag-immunized animals and were not significantly affected by the spatial separation of gag and RT genes from the env genes. Our results illustrate the importance of being cautious when formulating multivalent genetic vaccines and that it might be possible to overcome lost immune responses through spatial separation of vaccine antigens.

AIDS Vaccines↗
PubMed2005

In vitro simian virus 40 large tumor antigen expression correlates with differential immune responses following DNA immunization.

Simian virus 40 (SV40) contains an essential protein, large tumor antigen (Tag), which assists in viral replication and causes cell transformation and immortalization. Our laboratory has examined plasmid DNA, expressing SV40 Tag under two different promoters, for use in potential cancer vaccination strategies. One plasmid, pSV3-neo, failed to induce SV40 Tag antibody, produced a weak cell-mediated response, and only partial protection in murine experimental tumor challenge systems. The second plasmid, pCMV-Tag, induced antibodies to SV40 Tag, produced a robust cell-mediated response, and invoked complete tumor immunity in vivo. The induction of CD4+ and CD8+ T cell responses following plasmid DNA immunization and tumor cell challenge reflected a type 1 cytokine secretion profile. Our hypothesis for this differential immune response is that pCMV-Tag exhibits a higher level of transgene expression due to a more efficient promoter. We determined that pCMV-Tag levels of SV40 Tag mRNA and protein expression were higher when compared to pSV3-neo. A threshold amount of SV40 Tag may be required to stimulate antibody production and provide complete systemic tumor immunity.

Animals↗
PubMed2006

A single immunization with a recombinant canine adenovirus expressing the rabies virus G protein confers protective immunity against rabies in mice.

Rabies vaccines based on live attenuated rabies viruses or recombinant pox viruses expressing the rabies virus (RV) glycoprotein (G) hold the greatest promise of safety and efficacy, particularly for oral immunization of wildlife. However, while these vaccines induce protective immunity in foxes, they are less effective in other animals, and safety concerns have been raised for some of these vaccines. Because canine adenovirus 2 (CAV2) is licensed for use as a live vaccine for dogs and has an excellent efficacy and safety record, we used this virus as an expression vector for the RVG. The recombinant CAV2-RV G produces virus titers similar to those produced by wild-type CAV2, indicating that the RVG gene does not affect virus replication. Comparison of RVG expressed by CAV2-RV G with that of vaccinia-RV G recombinant virus (V-RG) revealed similar amounts of RV G on the cell surface. A single intramuscular or intranasal immunization of mice with CAV2-RVG induced protective immunity in a dose-dependent manner, with no clinical signs or discomfort from the virus infection regardless of the route of administration or the amount of virus.

Adenoviruses, Canine↗
PubMed2005

Improving recombinant MVA immune responses: potentiation of the immune responses to HIV-1 with MVA and DNA vectors expressing Env and the cytokines IL-12 and IFN-gamma.

Recombinants based on vaccinia virus vectors, especially on the highly attenuated modified vaccinia virus Ankara (MVA) strain, are now being tested in clinical trials for safety and immunogenicity, using prime/boost heterologous regimes of vaccination. Due to the limited replication capacity of MVA, it is necessary to develop procedures that can enhance the specific cellular immune responses to the recombinant antigen delivered by the MVA vector. In this investigation, we have characterized the systemic immune responses in BALB/c mice using interferon-gamma (IFN-gamma) or interleukin-12 (IL-12) in an adjuvant-like manner elicited by MVA recombinants or naked DNA vectors expressing one of those cytokines in combination with the human immunodeficiency virus type 1 (HIV-1) envelope (Env) as antigen. In infected mice, virus gene expression in splenocytes and levels of cytokines IFN-gamma and IL-12 in serum were maximal by 6h post-infection (hpi) with MVA recombinants expressing IFN-gamma (MVAIFN-gamma) or IL-12 (MVAIL-12). In the infected animals, co-expression of HIV-1 env (MVAENV) and either IFN-gamma or IL-12 from MVA recombinants produced a two and three-fold increase of anti-env CD8+ T cell response, respectively. When priming was carried out with DNA vectors expressing HIV-1 env and either IFN-gamma or IL-12, the magnitude of the specific anti-env CD8+ T cell stimulation after MVAENV booster was further enhanced. Our findings revealed that IFN-gamma or IL-12 can be used to potentiate the cellular immune response to HIV-1 env, when delivered either from a single MVA recombinant or from a DNA vector. The increment of the CD8+ T cell response was higher in a DNA/MVA prime/boost protocol. Thus, the immune response of MVA vectors can be improved with the co-delivery of the cytokines IFN-gamma or IL-12.

AIDS Vaccines↗
PubMed2002

Immunity and schizophrenia: autoimmunity, cytokines, and immune responses.

As is evident from the present account, there is no single or persuasive argument that signals emanating from the immune system are directly involved in the etiology of schizophrenia. We do not even know if we are dealing with a single disorder with a single causality; almost certainly we are not. The precise etiology of schizophrenia, as with so many neurological disorders, remains obscure. However, there is abundant evidence in schizophrenia of mutual dysregulation of neuronal function and immune system activity. Although this evidence is not always consistent, a pattern emerges suggesting aspects of immune activity being involved in the pathology of neuronal development that characterizes schizophrenia. Exposure to infective agents, HLA associations, autoimmune associations, disturbances in lymphocyte populations, and cytokine imbalances with a skew toward Th2 activity are supportive of this view. That the evidence is not always consistent is a testament to the complexity and heterogeneity of the disorder, to confounding by antipsychotics that themselves are immunomodulatory, and to the multifaceted nature, with all its checks and balances, of the immune system itself.

Animals↗
PubMed2002

Enhanced expression of iNOS intratumorally and at the immunization site after immunization with IFNgamma-secreting rat glioma cells.

Nitric oxide (NO) can modulate both tumor growth and antitumor immune responses. In order to elucidate the mechanism of curative therapeutic immunization with IFNgamma-producing glioma cells, we examined the expression of inducible nitric oxide synthase (iNOS) in tissue sections from immunized animals. There was a significantly enhanced iNOS expression both intratumorally and at the immunization site. Although the mechanisms behind this dual expression of iNOS most probably are different, our results suggest a role for NO in both the induction and execution of the antitumor response.

Animals↗
PubMed2001

Manipulating the immune system: humoral versus cell-mediated immunity.

Many of the vaccines in use today were designed on an empirical basis with little understanding of the mechanism of protective immunity or knowledge of the protective antigens. Certain of these vaccines, based on killed or attenuated bacteria or viruses, are associated with unacceptable side-effects. New generation vaccines based on recombinant proteins or naked DNA have considerably improved safety profiles, but are often poorly immunogenic, especially when administered by mucosal routes. This is a particular problem with oral delivery; where high doses of antigen are required to generate even modest immune responses. In contrast, nasal delivery of antigens with a range of adjuvants or delivery systems has been shown to generate relatively potent immune responses and to protect against infection in animal models. Advances in immunology have demonstrated that a variety of cellular and humoral immune effector mechanisms, that are regulated by distinct Th1 and Th2 subtypes of T cells, mediate protection against different infectious diseases. The identification of adjuvants and immunomodulators, that can promote the selective induction of these distinct populations of T cells, has now made it possible to rationally design safe and effective mucosal vaccines against a range of infectious diseases of man.

Adjuvants, Immunologic↗
PubMed1999

Enhancement of mucosal immune responses to the influenza virus HA protein by alternative approaches to DNA immunization.

DNA immunization provides many advantages as an approach to prevent infectious diseases. However, although previous studies using this approach have demonstrated immune responses in serum, they were not successful in inducing significant levels of antibodies in secretions. In this study, plasmid DNAs expressing the influenza virus hemagglutinin glycoprotein have been evaluated for their ability to induce antibody responses in serum and saliva when used alone or along with either liposomes or bioadhesive polymers as mucosal delivery vehicles. Significant levels of virus-specific Ig in serum as well as secretory IgA in saliva were detected in mice following mucosal DNA immunization. These antibodies were found to block the infectivity of the virus using a plaque reduction assay. Our findings thus indicate that mucosal DNA immunization with specific delivery systems can elicit virus-specific antibody responses in serum as well as IgA responses at mucosal surfaces.

Adhesives↗
PubMedDate not supplied

A natural cytokine mixture (IRX-2) and interference with immune suppression induce immune mobilization and regression of head and neck cancer.

Prior studies indicate that combination immunotherapy of squamous cell cancer (SCC) of head and neck (H&N) with cytokines is feasible (Hadden et al., 1994). To induce immune regression of H&N SCC 20 stage II-IV patients received 3 weeks prior to surgery low dose cyclophosphamide (300 mg/M2), then 10 daily perilymphatic injections of a natural cytokine mixture (IRX-2)(150 units of IL-2 equivalence) and daily oral indomethacin and zinc. Tumor responses, T-lymphocyte and subset counts, and toxicity were monitored. Six patients had major clinical responses (both complete [CR] and partial [PR]) without major toxicity. Five of 20 patients were lymphocytopenic (1242 +/- 88 mm3) prior to treatment and the immunotherapy induced marked significant increases in total lymphocyte counts, CD3+ T-cells, and both CD4+ and CD8+ T-cells as well as a population of CD3+, CD4-, and CD8- lymphocytes. The post treatment specimen of 18/20 patients showed histologically tumor fragmentation, overall reduction and diffuse infiltration with lymphocytes and plasma cells. Histologic tumor reductions in these patients averaged 44% and the lymphoid infiltration increased 4.7 fold from 9-42%. The immune infiltration of the tumor reflects varying degrees of both T- and B-cells and indicates immunization to the tumor. The immunization achieved may improve clinical control of H&N SCC by improving the possibility that surgical resection of advanced loco-regional disease will leave no viable tumor.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Nasal or intramuscular immunization of mice with influenza subunit antigen and the B subunit of Escherichia coli heat-labile toxin induces IgA- or IgG-mediated protective mucosal immunity.

Local mucosal IgA antibodies play a central role in protection of the respiratory tract against influenza virus infection. Therefore, new-generation influenza vaccines should aim at stimulating not only systemic, but also local antibody responses. Previously, we demonstrated that the recombinant B subunit of the Escherichia coli heat-labile toxin (LTB) is a potent adjuvant towards nasally administered influenza subunit antigen. Here, we investigated the protection conferred by LTB-supplemented influenza subunit antigen given intranasally (i.n.) or intramuscularly (i.m.) to mice. Both i.n. and i.m. immunization with subunit antigen and LTB completely protected the animals against viral infection. Protection upon i.n. immunization was associated with the induction of antigen-specific serum IgG and mucosal IgA, whereas protection upon i.m. immunization correlated with strong serum and mucosal IgG, but not IgA responses. We conclude that LTB-supplemented influenza subunit antigen, given either i.n. or i.m, induces protective antibody-mediated mucosal immunity and thus represents a promising novel flu vaccine candidate.

Adjuvants, Immunologic↗
PubMed2001

Immunization of mice with lipopeptide antigens encapsulated in novel liposomes prepared from the polar lipids of various Archaeobacteria elicits rapid and prolonged specific protective immunity against infection with the facultative intracellular pathogen, Listeria monocytogenes.

Protective immunity to intracellular bacterial pathogens usually requires the participation of specific CD8+ T cells. Natural exposure of the host to sublethal infection, or vaccination with attenuated live vaccines are the most effective means of eliciting prolonged protective cell-mediated immunity against this class of pathogens. The ability to replace these immunization strategies with defined sub-unit vaccines would represent a major advance for clinical vaccinology. The present study examines the ability of novel liposomes, termed archaeosomes, made from the polar lipids of various Archaeobacteria to act as self-adjuvanting vaccine delivery vehicles for such defined acellular antigens. Using infection of mice with Listeria monocytogenes as a model system, this study clearly demonstrates the ability of defined, archaeosome-entrapped antigens to elicit rapid and prolonged specific immunity against a prototypical intracellular pathogen. In this regard, all of the tested archaeosomes were superior to conventional liposomes.

Animals↗
PubMed2001

Enhancement of the immunity to foot-and-mouth disease virus by DNA priming and protein boosting immunization.

Subunit vaccination is effective in eliciting humoral responses to a variety of viral antigens, however, it has not generated persistent protective immunity to foot-and-mouth disease virus (FMDV). In this study, we observed that priming mice with a DNA plasmid encoding VP1 of the FMDV O/Taiwan/97 capsid protein followed by boosting with a VP1 peptide conjugate (P29-KLH) resulted in production of not only high titers of antibodies but also antibodies with FMDV neutralizing activities. Moreover, the mice immunized in this manner cleared the virus from their sera in FMDV challenge experiments. Mice subjected to DNA plasmid priming and P29-KLH protein boosting had relatively higher ratio of IgG2a/IgG1 than those primed and boosted with P29-KLH conjugate. Addition of an oligodeoxynucleotide (ODN) containing immunostimulatory cytosine-phosphate-guanosine (CpG) motifs to P29-KLH conjugate also induced a higher ratio of IgG2a/IgG1 and significantly higher titer of neutralizing antibodies. These results indicate that treating animals with DNA plasmids priming and FMDV antigen(s) boosting may elicit immunity to FMD and this immune response may be augmented by CpG ODN.

Amino Acid Sequence↗
PubMedDate not supplied

Durable immunity and immunologic memory to a parasite antigen induced by somatic transgene immunization.

Somatic transgene immunization (STI) is an alternative approach to immunization mediated by inoculation of plasmid DNA. In the experiments presented here we show that inoculation of plasmid DNA carrying an immunoglobulin heavy chain gene under the control of tissue-specific regulatory elements, leads to immunity and persistent immunologic memory against a peptide epitope encoded in the third complementarity-determining region. The epitope consists in three repeats of the tetrapeptide Asn-Ala-Asn-Pro (NANP) and is the immunodominant B cell epitope expressed at the surface of Plasmodium falciparum malaria parasite. When inoculated directly in the spleen the plasmid DNA initiated a specific anti-NANP response which lasted for 2 years. During the initial phase of priming the anti-NANP response was higher than that induced by immunization with recombinant protein in immunologic adjuvants. The establishment of immunologic memory was probed by single booster injection at various times after priming. We found that STI induces persistent immunologic memory up to 2 years. The immunologic characteristics of this new model are examined with respect to the requirement for the induction of B cell memory.

Animals↗
PubMed1997

Adjuvants influence the quantitative and qualitative immune response in BALB/c mice immunized with respiratory syncytial virus FG subunit vaccine.

The ability of monophosphoryl lipid A (MPL), QS-21 and alum to alter the immunologic response to immunization with respiratory syncytial virus a chimeric FG construct (FG) subunit vaccine was examined in BALB/c mice. FG/MPL, FG/alum, and FG/MPL/QS-21 combinations increased non-neutralizing antibody response, while FG/QS-21 did not. FG subunit vaccine with MPL, QS-21, or both had cytokine responses more closely resembling primary infection than FG/alum, with decreased interleukin-4 mRNA levels and increased IgG2a isotype antibody. The lungs of the mice immunized with FG subunit vaccines showed a heightened inflammatory response to respiratory syncytial virus challenge as compared to live virus immunization. Adjuvants can be used to alter the humoral and cellular responses to RSV subunit immunization.

Adjuvants, Immunologic↗
PubMed1999

Induction of specific cell-mediated immunity in mice by oral immunization with Salmonella expressing Onchocerca volvulus glutathione S-transferase.

Cellular and humoral immune responses of mice to Onchocerca volvulus glutathione S-transferase (OvGST) presented via in vivo expression in attenuated Salmonella typhimurium were examined and compared with the same antigen administered by subcutaneous injection with Freund's adjuvant. After infection with recombinant S. typhimurium, maximal numbers of bacteria were recovered from the mesenteric lymph nodes and spleens during the second week postinfection. By weeks 3-4, bacteria were absent from these tissues. Splenocytes from mice infected with S. typhimurium expressing OvGST showed significant and specific proliferative responses to OvGST, whereas the non-recombinant S. typhimurium controls and those which received the antigen by subcutaneous injection with Freund's adjuvant did not. Mice infected with recombinant S. typhimurium had elevated IFN-gamma levels over non-recombinant S. typhimurium and placebo controls. but IL-4 and IL-5 levels were low and did not differ significantly between these groups. Antibody responses to OvGST antigen expressed by a recombinant Salmonella vaccine or delivered in a purified form with Freund's adjuvant were moderate to high. These data suggest that Salmonella can be used as a vaccine delivery vector that induces specific cellular and humoral immune responses to Onchocerca volvulus antigens. This is the first report to describe the successful application of a filarial antigen in a live-vector delivery system as well as the first recombinant based filarial vaccine to elicit a cellular immune response similar to that described for putative immune endemics.

Administration, Oral↗
PubMed1999

Immunization with influenza A virus hemagglutinin and neuraminidase produced in recombinant baculovirus results in a balanced and broadened immune response superior to conventional vaccine.

Influenza A virus hemagglutinin (HA) and neuraminidase (NA) from A/Nanchang/933/95 were expressed by recombinant baculovirus-infected insect cell lines. HA and NA were chromatographically purified then combined in a single vaccine preparation. Immunization of mice with this preparation resulted in high titers of antibodies to both HA and NA equivalent for each antigen to titers in animals immunized with either antigen alone. Anti-NA antibody titers, measured by either enzyme linked immunoabsorbant assay or neuraminidase inhibition test were higher in the combined recombinant vaccine than in conventional monovalent inactivated vaccine. There was no difference in the anti-HA antibody titers between these two vaccine preparations. Homotypic and closely related heterotypic infections were suppressed and greater reduction in viral replication was observed following a distantly related heterotypic infectious challenge than was observed with conventional inactivated vaccine. The combined HA and NA vaccine takes advantage of the equivalent immunogenicity of dissociated HA and NA, to produce a broader and more balanced immune response to both antigens, without the HA-dominant antigenic competition that occurs with natural infection or immunization with conventional vaccine. Additionally, the recombinant baculovirus expression system offers a reliable rapid production system without the use of massive numbers of embryonated chicken eggs. These studies in a mouse model system suggest that production of a combined HA and NA vaccine from recombinant baculovirus offers an improved alternative to conventional inactivated influenza vaccine.

Animals↗
PubMed2000

Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space.

According to the remodeling theory of aging we proposed several years ago, the current data on human immunosenescence depicts a complex scenario where clonotypical immunity deteriorates, while ancestral innate/natural immunity is largely conserved or even up-regulated with age. Under an evolutionary perspective, antigens are the cause of a persistent life-long antigenic stress, responsible for the accumulation of effector CD8+/CD28- T cells, the decrease of naive T cells (CD95-) and the marked shrinkage of T cell repertoire with age. Concomitantly, NK cytotoxicity, chemotaxis, phagocytosis and complement activities remain unaffected or negligibly affected, in comparison to clonotypical immunity. Thus, immunosenescence is not a random deteriorative phenomenon but appears to inversely recapitulate an evolutionary pattern. On the whole, immunosenescence can be envisaged as the result of the continuous challenge of the unavoidable exposure to a variety of potential antigens (viruses, bacteria, but also food and self molecules among others). From this perspective antigens are nothing else than a particular type of stressor and immunosenescence appears to be the price paid to immunological memory, i.e. one of the main characteristics of the most evolutionary recent and sophisticated type of immunity. Together with the age-related thymic involution, and the consequent age-related decrease of thymic output of new T cells, this situation leaves the body practically devoid of virgin T cells, and thus likely more prone to a variety of infectious and non infectious diseases.

Aged↗
PubMed2003

Passive immunity and serological immune response in dairy calves associated with natural Giardia duodenalis infections.

In a previous study, Giardia infection patterns were studied in newborn dairy calves over a 4-month period. Chronic Giardia infections were observed in all calves with initial cyst excretion occurring at approximately 1 month of age. In the work presented here, the passive immunity and serological immune response associated with these Giardia infections were examined. Colostrum and milk samples were collected from the dams of these calves, and monthly serum samples were collected from each calf. The colostrum, milk and sera samples were analyzed by ELISA and Western blot for the presence of anti-Giardia IgG antibodies. In addition, the in vitro anti-Giardia activity of milk and colostrum was examined using a miniculture adherence assay. When examined by ELISA, mean anti-Giardia antibody titres were found to be significantly higher in colostrum compared to milk. The monthly mean serum antibody titres in the calves were not found to differ significantly at any time point during the study. Western blot analysis revealed that colostrum from the dams reacted strongly with many different Giardia antigens between 205 and 7.5kDa, while milk reacted with few antigens in the same size range. Sera collected from the calves when 30 and 60 days of age reacted with few Giardia antigens, but as the calves aged, IgG antibodies in their sera began to react with antigens of 21, 50, 65, 73 and 79kDa. The miniculture adherence assay demonstrated that colostrum had significantly more anti-Giardia activity in vitro compared to milk. These results suggest that the calves in this dairy did not mount a significant humoral immune response against Giardia following infection. However, colostrum contained a high level of anti-Giardia antibodies and exhibited anti-Giardia activity in vitro. Therefore, colostrum may have the potential to provide initial protection against Giardia infections in calves, but the lack of a strong, specific humoral immune response by these calves could account for the high prevalence and chronic duration of the infections.

Animals↗