scholarly journals NSP4 as Adjuvant for Immunogenicity and Design of Effective Therapeutic HPV16 E6/E7/L1 DNA Vaccine in Tumoric and Healthy C57BL/6 Mice

2021 ◽  
Author(s):  
Sahar Sadr-Momtaz ◽  
Maryam Aftabi ◽  
Emad Behboudi ◽  
Malihe Naderi ◽  
Anahita Hashemzadeh-Omran ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dna Vaccine ◽  
Therapeutic Vaccine ◽  
Hpv Infection ◽  
Interleukin 4 ◽  
Spleen Cells ◽  
Hpv16 E6 ◽  
Hpv Dna ◽  
Healthy Control ◽  
Ifn Γ

Abstract Introduction: In humans, approximately 5% of all cancers are attributable to HPV infection. Prophylactic vaccines can inhibit viral migration and persistence. However, requirement to develop therapeutic treatments prevails. To achieve this goal, we designed a therapeutic HPV DNA vaccine encoding a construct of E6/E7/L1 and used NSP4 antigen as adjuvant to assess efficiency of this construct in generating antigen-specific antitumor immune responses.Material and Methods: Sixty female C57BL/6 mice (6–8 weeks old) were purchased from Institute Pasteur of Iran. 30 of them became cancerous, but 30 of them were healthy control. To amplify E6/E7/L1-pcDNA3, NSP4-pcDNA3, expression vector of DH5α and TC-1 cell line were used to generate a tumor. Mice were immunized with HPV DNA vaccine. Cell proliferation was assessed by MTT assay. Finally, we assessed cytokine responses (IL-2, IL-4, INF- γ), in the serum of mice spleen cells.Result: Mice receiving the NSP4/E6-E7-L1 vaccine had the highest stimulatory index compared to other groups but it was not significant. Interleukin 4/12 and INF-γ production were significantly higher in E6-E7-L1 / NSP4 group and E6-E7-L1 group compared to other groups (P <0.05). Among different groups, E6/E7/L1 + NSP4 group was able to slow down the tumor growth process, but it was not significant (p>0.05). Among the cytokines mentioned, IFN-γ and IL-12 are among the cytokines that stimulate the Th1 pathway and IL-4 cytokine stimulates the Th2 pathway and B lymphocytes.Conclusion: Our data suggest that present vaccine can stimulate innate and acquired immunity response, and can be a therapeutic vaccine in the tumoric mice.

scholarly journals Predominance of CD4 Th1 and CD8 Tc1 Cells Revealed by Characterization of the Cellular Immune Response Generated by Immunization with a DNA Vaccine Containing a Trypanosoma cruzi Gene

1999 ◽  
Vol 67 (8) ◽  
pp. 3855-3863 ◽  
Author(s):  
Mauricio M. Rodrigues ◽  
Marcelo Ribeirão ◽  
Vera Pereira-Chioccola ◽  
Laurent Renia ◽  
Fabio Costa
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Dna Vaccine ◽  
Cd8 T Cells ◽  
Catalytic Domain ◽  
Therapeutic Vaccine ◽  
Cell Types ◽  
Interleukin 4 ◽  
Ifn Γ

ABSTRACT Immunization with a plasmid DNA containing the gene encoding the catalytic domain of trans-sialidase (TS) elicits protective immune responses against experimental Trypanosoma cruziinfection. As several studies provided strong evidence that during infection CD4 Th1 and CD8 T cytotoxic type 1 (Tc1) cells are important factors in host resistance, the present study was designed to evaluate which T-cell types were activated in DNA-vaccinated BALB/c mice. We found that bulk cells from DNA-immunized mice had CD4 and CD8 T cells that produced gamma interferon (IFN-γ) but not interleukin-4 (IL-4) or IL-10. To characterize the TS-specific T cells at the clonal level, we generated CD4 and CD8 clones. We obtained cytotoxic CD4 clones of the Th1 type that secreted large amounts of IFN-γ but not IL-4 or IL-10. Unexpectedly, we obtained other CD4 clones with a Th2 phenotype, secreting IL-4 and IL-10 but not IFN-γ. All CD8 clones were cytotoxic and produced IFN-γ. IL-4 and IL-10 were not secreted by these cells. Using synthetic peptides, we determined a CD8 epitope recognized by several clones as being represented by amino acids IYNVGQVSI. The antiparasitic activity of a CD4 Th1 and a CD8 Tc1 clone was assessed in vitro. CD4 or CD8 T cells significantly inhibited T. cruzidevelopment in infected macrophages or fibroblasts, respectively. We concluded that DNA vaccine efficiently generates potentially protective CD4 Th1 and CD8 Tc1 cells specific for a T. cruzi antigen, therefore reinforcing the possibility of using this strategy for developing a preventive or therapeutic vaccine against Chagas’ disease.

scholarly journals Predictors of the Therapeutic Response to Intralesional Bivalent HPV Vaccine in Wart Immunotherapy

Vaccines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1280
Author(s):  
Noha M. Hammad ◽  
Ayman Marei ◽  
Gamal El-Didamony ◽  
Zeinb Mortada ◽  
Mona Elradi ◽  
...  
Keyword(s):  
Hpv Vaccine ◽  
Ex Vivo ◽  
Hpv Infection ◽  
Interleukin 4 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Anogenital Warts ◽  
Healthy Control ◽  
Ifn Γ ◽  
And Control ◽  
Culture Supernatants

Variable intralesional immunotherapies have recently been proposed as a means of achieving a successful eradication of recurrent and recalcitrant human papillomavirus (HPV)-induced cutaneous and anogenital warts. The bivalent HPV vaccine is one of the newly proposed immunotherapeutic agents. We investigated the role of interleukin-4 (IL-4) and interferon-gamma (IFN-γ) as ex vivo immunologic predictors to estimate the response to the bivalent HPV vaccine as a potential immunotherapy for cutaneous and anogenital warts. Heparinized blood samples were withdrawn from forty patients with multiple recurrent recalcitrant cutaneous and anogenital warts and forty matched healthy control subjects. Whole blood cultures were prepared with and without bivalent HPV vaccine stimulation. Culture supernatants were harvested and stored for IL-4 and IFN-γ measurements using an enzyme-linked immunosorbent assay. A comparative analysis of IL-4 and IFN-γ levels in culture supernatants revealed a non-significant change between the patient and control groups. The bivalent HPV vaccine stimulated cultures exhibited a non-significant reduction in IL-4 levels within both groups. IFN-γ was markedly induced in both groups in response to bivalent HPV vaccine stimulation. The bivalent HPV vaccine can give a sensitive IFN-γ immune response ex vivo, superior to IL-4 and sufficient to predict both the successful eradication of HPV infection and the ultimate clearance of cutaneous and anogenital warts when the bivalent HPV vaccine immunotherapy is applied.

scholarly journals Gamma Interferon Produced by Antigen-Specific CD4+ T Cells Regulates the Mucosal Immune Responses to Citrobacter rodentium Infection

2010 ◽  
Vol 78 (6) ◽  
pp. 2653-2666 ◽  
Author(s):  
Hideyuki Shiomi ◽  
Atsuhiro Masuda ◽  
Shin Nishiumi ◽  
Masayuki Nishida ◽  
Tetsuya Takagawa ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Gamma Interferon ◽  
Immune Defense ◽  
Interleukin 4 ◽  
Mucosal Inflammation ◽  
Citrobacter Rodentium ◽  
Macrophage Phagocytosis ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the surface of intestinal epithelial cells and causes mucosal inflammation. This bacterium is an ideal model for investigating pathogen-host immune interactions in the gut. It is well known that gene transcripts for Th1 cytokines are highly induced in colonic tissue from mice infected with C. rodentium. However, it remains to be seen whether the Th1 or Th2 cytokines produced by antigen-specific CD4+ T cells provide effective regulation of the host immune defense against C. rodentium infection. To investigate the antigen-specific immune responses, C. rodentium expressing ovalbumin (OVA-C. rodentium), a model antigen, was generated and used to define antigen-specific responses under gamma interferon (IFN-γ)-deficient or interleukin-4 (IL-4)-deficient conditions in vivo. The activation of antigen-specific CD4+ T cells and macrophage phagocytosis were evaluated in the presence of IFN-γ or IL-4 in vitro. IFN-γ-deficient mice exhibited a loss of body weight and a higher bacterial concentration in feces during OVA-C. rodentium infection than C57BL/6 (wild type) or IL-4-deficient mice. This occurred through the decreased efficiency of macrophage phagocytosis and the activation of antigen-specific CD4+ T cells. Furthermore, a deficiency in antigen-specific CD4+ T-cell-expressed IFN-γ led to a higher susceptibility to mucosal and gut-derived systemic OVA-C. rodentium infection. These results show that the IFN-γ produced by antigen-specific CD4+ T cells plays an important role in the defense against C. rodentium.

scholarly journals Bartonella henselae-Specific Cell-Mediated Immune Responses Display a Predominantly Th1 Phenotype in Experimentally Infected C57BL/6 Mice

2001 ◽  
Vol 69 (10) ◽  
pp. 6427-6433 ◽  
Author(s):  
Mardjan Arvand ◽  
Ralf Ignatius ◽  
Thomas Regnath ◽  
Helmut Hahn ◽  
Martin E. A. Mielke
Keyword(s):  
Immune Responses ◽  
Bartonella Henselae ◽  
Interleukin 4 ◽  
Infection Model ◽  
Antibody Concentration ◽  
Specific Cell ◽  
Spleen Cells ◽  
Viable Bacteria ◽  
Igg Isotypes

ABSTRACT Immune responses of the immunocompetent host to Bartonella henselae infection were investigated in the murine infection model using C57BL/6 mice. Following intraperitoneal infection with human-derived B. henselae strain Berlin-1, viable bacteria could be recovered from livers and spleens during the first week postinfection, while Bartonella DNA remained detectable by PCR in the liver for up to 12 weeks after infection. Granulomatous lesions developed in livers of infected mice, reached maximal density at 12 weeks after infection, and persisted for up to 20 weeks, indicating that B. henselae induced a chronic granulomatous hepatitis in the immunocompetent murine host. T-cell-mediated immune responses were analyzed in vitro by means of spleen cell proliferation and cytokine release assays as well as analysis of immunoglobulin G (IgG) isotypes. Spleen cells from infected mice proliferated specifically upon stimulation with heat-killedBartonella antigen. Proliferative responses were mainly mediated by CD4+ T cells, increased during the course of infection, peaked at 8 weeks postinfection, and decreased thereafter. Gamma interferon, but not interleukin-4, was produced in vitro by spleen cells from infected animals upon stimulation withBartonella antigens. Bartonella-specific IgG was detectable in serum of infected mice by 2 weeks, and the antibody concentration peaked at 12 weeks postinfection. IgG2b was the prominent isotype among the Bartonella-specific serum IgG antibodies. These data indicate that B. henselaeinduces cell-mediated immune responses with a Th1 phenotype in immunocompetent C57BL/6 mice.

scholarly journals Equine Neonates Have Attenuated Humoral and Cell-Mediated Immune Responses to a Killed Adjuvanted Vaccine Compared to Adult Horses

2010 ◽  
Vol 17 (12) ◽  
pp. 1896-1902 ◽  
Author(s):  
Clare Ryan ◽  
Steeve Giguère
Keyword(s):  
Immune Responses ◽  
Gamma Interferon ◽  
Maternal Antibody ◽  
Serum Immunoglobulin ◽  
Interleukin 4 ◽  
Respiratory Pathogens ◽  
Adjuvanted Vaccine ◽  
Specific Serum ◽  
Ifn Γ ◽  
Viral Respiratory

ABSTRACT The objectives of this study were to compare relative vaccine-specific serum immunoglobulin concentrations, vaccine-specific lymphoproliferative responses, and cytokine profiles of proliferating lymphocytes between 3-day-old foals, 3-month-old foals, and adult horses after vaccination with a killed adjuvanted vaccine. Horses were vaccinated intramuscularly twice at 3-week intervals with a vaccine containing antigens from bovine viral respiratory pathogens to avoid interference from maternal antibody. Both groups of foals and adult horses responded to the vaccine with a significant increase in vaccine-specific IgGa and IgG(T) concentrations. In contrast, only adult horses and 3-month-old foals mounted significant vaccine-specific total IgG, IgGb, and IgM responses. Vaccine-specific concentrations of IgM and IgG(T) were significantly different between all groups, with the highest concentrations occurring in adult horses, followed by 3-month-old foals and, finally, 3-day-old foals. Only the adult horses mounted significant vaccine-specific lymphoproliferative responses. Baseline gamma interferon (IFN-γ) and interleukin-4 (IL-4) concentrations were significantly lower in 3-day-old foals than in adult horses. Vaccination resulted in a significant decrease in IFN-γ concentrations in adult horses and a significant decrease in IL-4 concentrations in 3-day-old foals. After vaccination, the ratio of IFN-γ/IL-4 in both groups of foals was significantly higher than that in adult horses. The results of this study indicate that the humoral and lymphoproliferative immune responses to this killed adjuvanted vaccine are modest in newborn foals. Although immune responses improve with age, 3-month-old foals do not respond with the same magnitude as adult horses.

scholarly journals Delivery of Cytokines by Recombinant Virus in Early Life Alters the Immune Response to Adult Lung Infection

2010 ◽  
Vol 84 (10) ◽  
pp. 5294-5302 ◽  
Author(s):  
James A. Harker ◽  
Debbie C. P. Lee ◽  
Yuko Yamaguchi ◽  
Belinda Wang ◽  
Alexander Bukreyev ◽  
...  
Keyword(s):  
Immune Responses ◽  
Secondary Infection ◽  
Interleukin 4 ◽  
Newborn Mice ◽  
Recombinant Viruses ◽  
T Helper 2 ◽  
Th1 And Th2 Cytokines ◽  
Ifn Γ ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is the main cause of bronchiolitis, the major cause of hospitalization of infants. An ideal RSV vaccine would be effective for neonates, but the immune responses of infants differ markedly from those of adults, often showing a bias toward T-helper 2 (Th2) responses and reduced gamma interferon (IFN-γ) production. We previously developed recombinant RSV vectors expressing IFN-γ and interleukin-4 (IL-4) that allow us to explore the role of these key Th1 and Th2 cytokines during infection. The aim of the current study was to explore whether an immunomodulation of infant responses could enhance protection. The expression of IFN-γ by a recombinant RSV vector (RSV/IFN-γ) attenuated primary viral replication in newborn mice without affecting the development of specific antibody or T-cell responses. Upon challenge, RSV/IFN-γ mice were protected from the exacerbated disease observed for mice primed with wild-type RSV; however, antiviral immunity was not enhanced. Conversely, the expression of IL-4 by recombinant RSV did not affect virus replication in neonates but greatly enhanced Th2 immune responses upon challenge without affecting weight loss. These studies demonstrate that it is possible to manipulate infant immune responses by using cytokine-expressing recombinant viruses and that neonatal deficiency in IFN-γ responses may lead to enhanced disease during secondary infection.

scholarly journals Bovine Immune Response to Inoculation with Neospora caninum Surface Antigen SRS2 Lipopeptides Mimics Immune Response to Infection with Live Parasites

2008 ◽  
Vol 15 (4) ◽  
pp. 659-667 ◽  
Author(s):  
Timothy V. Baszler ◽  
Varda Shkap ◽  
Waithaka Mwangi ◽  
Christopher J. Davies ◽  
Bruce A. Mathison ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Dna Vaccine ◽  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Neospora Caninum ◽  
Lymphocyte Activation ◽  
T Lymphocyte Activation ◽  
T Lymphocyte Proliferation ◽  
Ifn Γ

ABSTRACT Infection of cattle with Neospora caninum protozoa, the causative agent of bovine protozoal abortion, results in robust cellular and humoral immune responses, particularly CD4+ T-lymphocyte activation and gamma interferon (IFN-γ) secretion. In the present study, N. caninum SRS2 (NcSRS2) T-lymphocyte-epitope-bearing subunits were incorporated into DNA and peptide preparations to assess CD4+ cell proliferation and IFN-γ T-lymphocyte-secretion immune responses in cattle with predetermined major histocompatibility complex (MHC) genotypes. In order to optimize dendritic-cell processing, NcSRS2 DNA vaccine was delivered with granulocyte macrophage-colony-stimulating factor and Flt3 ligand adjuvant. The synthesized NcSRS2 peptides were coupled with a palmitic acid molecule (lipopeptide) and delivered with Freund's adjuvant. Cattle vaccinated with NcSRS2 DNA vaccine alone did not induce T-lymphocyte activation or IFN-γ secretion, whereas subsequent booster inoculation with NcSRS2-lipopeptides induced robust NcSRS2-specific immune responses. Compared to the response in control animals, NcSRS2-lipopeptide-immunized cattle had significantly increased NcSRS2-specific T-lymphocyte proliferation, numbers of IFN-γ-secreting peripheral blood mononuclear cells, and immunoglobulin G1 (IgG1) and IgG2a antibody levels. The findings show that N. caninum NcSRS2 subunits bearing T-lymphocyte epitopes induced cell-mediated immune responses similar to the protective immune responses previously described against live parasite infection, namely T-lymphocyte activation and IFN-γ secretion. The findings support the investigation of NcSRS2 immunogens for protection against N. caninum-induced fetal infection and abortion in cattle.

scholarly journals Reciprocal Protective Immunity againstBordetella pertussis and Bordetella parapertussis in a Murine Model of Respiratory Infection

2001 ◽  
Vol 69 (11) ◽  
pp. 6981-6986 ◽  
Author(s):  
Mineo Watanabe ◽  
Masaaki Nagai
Keyword(s):  
Immune Response ◽  
Respiratory Infection ◽  
Murine Model ◽  
Protective Immunity ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Spleen Cells ◽  
Bordetella Parapertussis ◽  
Ifn Γ

ABSTRACT The protective immunity induced by infection with Bordetella pertussis and with Bordetella parapertussis was examined in a murine model of respiratory infection. Convalescent mice that had been infected by aerosol with B. pertussis or with B. parapertussis exhibited a protective immune response against B. pertussis and also against B. parapertussis. Anti-filamentous hemagglutinin (anti-FHA) serum immunoglobulin G (IgG) and anti-FHA lung IgA antibodies were detected in both mice infected with B. pertussis and those infected with B. parapertussis. Antibodies against pertussis toxin (anti-PT) and against killed B. pertussis cells were detected in mice infected with B. pertussis. Pertactin-specific antibodies and antibodies against killed B. parapertussis cells were detected in mice infected with B. parapertussis. Spleen cells from mice infected with B. pertussis secreted interferon-γ (IFN-γ) in response to stimulation by FHA or PT. Spleen cells from mice infected with B. parapertussis also secreted IFN-γ in response to FHA. Interleukin-4 was not produced in response to any of the antigens tested. The profiles of cytokine secretion in vitro revealed induction of a Th1-biased immune response during convalescence from infection by B. pertussis and byB. parapertussis. It is possible that Th1 and Th2 responses against FHA might be related to the reciprocal protection achieved in our murine model.

scholarly journals Th1 Cytokine Patterns in Cervical Human Papillomavirus Infection

1999 ◽  
Vol 6 (5) ◽  
pp. 751-755 ◽  
Author(s):  
Mark Scott ◽  
Daniel P. Stites ◽  
Anna-Barbara Moscicki
Keyword(s):  
Human Papillomavirus ◽  
Hpv Infection ◽  
Interleukin 4 ◽  
Cell Mediated Immunity ◽  
Cross Sectional ◽  
Hpv Dna ◽  
Reverse Transcription Pcr ◽  
Th1 Cytokine ◽  
Cervical Cells ◽  
Cervical Human Papillomavirus

ABSTRACT The host’s immune response to cervical human papillomavirus (HPV) infection is poorly understood. In a longitudinal cohort of women with cervical HPV infections, defined by PCR-based HPV DNA testing, we used exfoliated cervical cells and reverse transcription-PCR to examine the cervical mucosal mRNA expression of cytokines involved in regulating cell-mediated immunity. We identified seven HPV-positive subjects who were found to have cleared their HPV infections 4 months later. In all seven, a T-helper type 1 (Th1) cytokine pattern (expression of gamma interferon and absence of interleukin-4) preceded clearance. The more variable cytokine patterns seen in HPV-negative subjects suggest that the Th1 pattern in the women with subsequent clearance was a response to the HPV infection. This contention is supported by additional cross-sectional data showing a Th1 pattern in a majority of HPV-positive women. This study establishes a feasible means for assessing local cytokine expression in the cervical milieu and demonstrates that a Th1 cytokine response is associated with subsequent clearance of cervical HPV infection.

scholarly journals Signaling via Interleukin-4 Receptor α Chain Is Required for Successful Vaccination against Schistosomiasis in BALB/c Mice

2001 ◽  
Vol 69 (1) ◽  
pp. 228-236 ◽  
Author(s):  
Adrian P. Mountford ◽  
Karen G. Hogg ◽  
Patricia S. Coulson ◽  
Frank Brombacher
Keyword(s):  
Immune Responses ◽  
Protective Immunity ◽  
Interleukin 4 ◽  
Lymphoid Tissues ◽  
Partial Protection ◽  
Exposure Site ◽  
Ifn Γ ◽  
Α Chain ◽  
Interleukin 4 Receptor ◽  
Effector Response

ABSTRACT Although protective immunity in C57BL/6 mice induced by a single dose of the radiation-attenuated schistosome vaccine is believed to be mediated by Th1-type immune responses, we here report that in BALB/c mice protection can also depend upon signaling via the interleukin-4 (IL-4) receptor which conventionally governs the development of Th2-type immune responses. We show that in BALB/c mice deficient for the IL-4 receptor α chain (IL-4Rα−/−), which are unresponsive to IL-4 and IL-13, vaccine-induced protection is abrogated compared with that in wild-type (WT) mice. In vaccinated IL-4Rα−/− mice, IL-12p40 production by cells from the skin exposure site was elevated, although gamma interferon (IFN-γ) production in draining lymphoid tissues was similar in WT and IL-4Rα−/− mice. Nevertheless, the effector response in IL-4Rα−/− mice was Th1 biased with elevated IFN-γ in the lungs and higher immunoglobulin G2a (IgG2a) and IgG2b titers but negligible quantities of Th2-associated IgG1 and IgE. Interestingly, levels of IL-4 were equivalent in WT and IL-4Rα−/−mice, indicating that Th2 responses were not dependent upon signaling by IL-4 or IL-13. No differences in the phenotype and composition of the pulmonary effector mechanism that might explain the failure to induce protection in IL-4Rα−/− mice were detected. However, passive transfer of partial protection to naive IL-4Rα−/− mice, using serum from vaccinated WT mice, indicates that Th2-associated antibodies such as IgG1 have a role in parasite elimination in BALB/c strain mice and that signaling via IL-4R can be an important factor in the generation of protection.

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