scholarly journals A Canine-Directed Chimeric Multi-Epitope Vaccine Induced Protective Immune Responses in BALB/c Mice Infected with Leishmania infantum

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 350 ◽  
Author(s):  
Maria Agallou ◽  
Maritsa Margaroni ◽  
Stathis D. Kotsakis ◽  
Evdokia Karagouni
Keyword(s):  
T Cells ◽  
T Cell ◽  
Visceral Leishmaniasis ◽  
Immune Responses ◽  
Leishmania Infantum ◽  
Parasite Burden ◽  
Significant Loss ◽  
T Cell Epitopes ◽  
Heparin Binding ◽  
Short Term

Leishmaniases are complex vector-borne diseases caused by intracellular parasites of the genus Leishmania. The visceral form of the disease affects both humans and canids in tropical, subtropical, and Mediterranean regions. One health approach has suggested that controlling zoonotic visceral leishmaniasis (ZVL) could have an impact on the reduction of the human incidence of visceral leishmaniasis (VL). Despite the fact that a preventive vaccination could help with leishmaniasis elimination, effective vaccines that are able to elicit protective immune responses are currently lacking. In the present study, we designed a chimeric multi-epitope protein composed of multiple CD8+ and CD4+ T cell epitopes which were obtained from six highly immunogenic proteins previously identified by an immunoproteomics approach, and the N-termini of the heparin-binding hemagglutinin (HBHA) of Mycobacterium tuberculosis served as an adjuvant. A preclinical evaluation of the candidate vaccine in BALB/c mice showed that when it was given along with the adjuvant Addavax it was able to induce strong immune responses. Cellular responses were dominated by the presence of central and effector multifunctional CD4+ and CD8+ T memory cells. Importantly, the vaccination reduced the parasite burden in both short-term and long-term vaccinated mice challenged with Leishmania infantum. Protection was characterized by the continuing presence of IFN-γ+TNFα+-producing CD8+ and CD4+ T cells and increased NO levels. The depletion of CD8+ T cells in short-term vaccinated mice conferred a significant loss of protection in both target organs of the parasite, indicating a significant involvement of this population in the protection against L. infantum challenge. Thus, the overall data could be considered to be a proof-of-concept that the design of efficacious T cell vaccines with the help of reverse vaccinology approaches is possible.

scholarly journals Multifunctional T Cell Response to DosR and Rpf Antigens Is Associated with Protection in Long-Term Mycobacterium tuberculosis-Infected Individuals in Colombia

2016 ◽  
Vol 23 (10) ◽  
pp. 813-824 ◽  
Author(s):  
Leonar Arroyo ◽  
Mauricio Rojas ◽  
Kees L. M. C. Franken ◽  
Tom H. M. Ottenhoff ◽  
Luis F. Barrera
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
T Cell Response ◽  
Short Term ◽  
Content Type ◽  
Long Term Culture

ABSTRACTMultifunctional T cells have been shown to be protective in chronic viral infections. In mycobacterial infections, however, evidence for a protective role of multifunctional T cells remains inconclusive. Short-term cultures of peripheral blood mononuclear cells stimulated with theMycobacterium tuberculosisRD1 antigens 6-kDa early secretory antigenic target (ESAT6) and 10-kDa culture filtrate antigen (CFP10), which are induced in the early infection phase, have been mainly used to assess T cell multifunctionality, although long-term culture assays have been proposed to be more sensitive than short-term assays for assessment of memory T cells, which are essential for long-term immunity. Here we used a long-term culture assay system to study the T cell immune responses to theM. tuberculosislatency-associated DosR antigens and reactivation-associated Rpf antigens, compared to ESAT6 and CFP10, in patients with pulmonary tuberculosis (PTB) and household contacts of PTB patients with long-term latent tuberculosis infection (ltLTBI), in a community in whichM. tuberculosisis endemic. Our results showed that the DosR antigens Rv1737c (narK2) and Rv2029c (pfkB) and the Rv2389c (rpfD) antigen ofM. tuberculosisinduced higher frequencies of CD4+or CD8+mono- or bifunctional (but not multifunctional) T cells producing interferon gamma (IFN-γ) and/or tumor necrosis alpha (TNF-α) in ltLTBI, compared to PTB. Moreover, the frequencies of CD4+and/or CD8+T cells with a CD45RO+CD27+phenotype were higher in ltLTBI than in PTB. Thus, the immune responses to selected DosR and Rpf antigens may be associated with long-term latency, correlating with protection fromM. tuberculosisreactivation in ltLTBI. Further study of the functional and memory phenotypes may contribute to further discrimination between the different states ofM. tuberculosisinfections.

scholarly journals Immunodominance of Adenovirus-Derived CD8+ T Cell Epitopes Interferes with the Induction of Transgene-Specific Immunity in Adenovirus-Based Immunization

2017 ◽  
Vol 91 (20) ◽  
Author(s):  
Dominik Schöne ◽  
Camilla Patrizia Hrycak ◽  
Sonja Windmann ◽  
Dennis Lapuente ◽  
Ulf Dittmer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Vaccine Development ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Content Type ◽  
Cell Responses

ABSTRACT Adenovirus (Ad)-based immunization is a popular approach in vaccine development, and Ad-based vectors are renowned for their potential to induce strong CD8+ T cell responses to the encoded transgene. Surprisingly, we previously found in the mouse Friend retrovirus (FV) model that Ad-based immunization did not induce CD8+ T cell responses to the FV Leader-Gag-derived immunodominant epitope GagL85–93. We show now that induction of GagL85–93-specific CD8+ T cells was highly effective when leader-Gag was delivered by plasmid DNA immunization, implying a role for Ad-derived epitopes in mediating unresponsiveness. By immunizing with DNA constructs encoding strings of GagL85–93 and the two Ad-derived epitopes DNA-binding protein418–426 (DBP418–426) and hexon486–494, we confirmed that Ad epitopes prevent induction of GagL85–93-specific CD8+ T cells. Interestingly, while DBP418–426 did not interfere with GagL85–93-specific CD8+ T cell induction, the H-2Dd-restricted hexon486–494 suppressed the CD8+ T cell response to the H-2Db-restricted GagL85–93 strongly in H-2b/d mice but not in H-2b/b mice. This finding indicates that competition occurs at the level of responding CD8+ T cells, and we could indeed demonstrate that coimmunization with an interleukin 2 (IL-2)-encoding plasmid restored GagL85–93-specific CD8+ T cell responses to epitope strings in the presence of hexon486–494. IL-2 codelivery did not restore GagL85–93 responsiveness in Ad-based immunization, however, likely due to the presence of further epitopes in the Ad vector. Our findings show that seemingly immunodominant transgene epitopes can be dominated by Ad-derived epitopes. These findings underline the importance of thorough characterization of vaccine vectors, and modifications of vectors or immunogens may be required to prevent impaired transgene-specific immune responses. IMPORTANCE Ad-based vectors are widely used in experimental preclinical and clinical immunization studies against numerous infectious agents, such as human immunodeficiency virus, Ebola virus, Plasmodium falciparum, or Mycobacterium tuberculosis. Preexisting immunity to Ad-based vectors is widely recognized as a hindrance to the widespread use of Ad-based vectors for immunizations in humans; however, our data show that an immune response to Ad-derived T cell epitopes can also result in loss or impairment of transgene-specific immune responses in prenaive vaccinees due to immune competition. Our results highlight that seemingly immunodominant epitopes may be affected by dominance of vector-derived epitopes, and modifications of the vector design or the immunogens employed in immunization may lead to more effective vaccines.

scholarly journals T-Cell Epitopes in Variable Segments ofChlamydia trachomatis Major Outer Membrane Protein Elicit Serovar-Specific Immune Responses in Infected Humans

2000 ◽  
Vol 68 (3) ◽  
pp. 1719-1723 ◽  
Author(s):  
Linette Ortiz ◽  
Mark Angevine ◽  
Seon-Kyeong Kim ◽  
David Watkins ◽  
Robert DeMars
Keyword(s):  
T Cells ◽  
T Cell ◽  
Membrane Protein ◽  
Immune Responses ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Major Outer Membrane Protein ◽  
T Cell Epitopes ◽  
Ofchlamydia Trachomatis ◽  
Variable Segment

ABSTRACT We previously identified 18 stimulatory Chlamydia trachomatis major outer membrane protein (MOMP) peptides containing at least 23 epitopes presented with various HLA class II allotypes. Only one peptide contained an epitope localized in a variable segment (VS2). Continued studies reported here identified a total of five VS peptides containing T-cell epitopes that are distributed among MOMPs VS1, VS2, and VS4. Only MOMP-primed T-cell cultures from subjects infected with serovar E responded to the serovar E VS peptides, while the response of such cultures to constant-segment peptides was independent of the infecting serovar. Furthermore, MOMP-primed T cells proliferated in response only to the VS peptides encoded in serovar E but not to the corresponding peptides derived from serovar F, I, or J, confirming that these responses were serovar specific.

scholarly journals 326 SARS-CoV-2 specific T-cells in TIL from patients with epithelial cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A352-A352
Author(s):  
Pedro Noronha ◽  
Georgia Paraschoudi ◽  
Eric Sousa ◽  
Jéssica Kamiki ◽  
Patrícia António ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Ifn Gamma ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune

BackgroundSARS-CoV-2 primarily infects the upper and lower airway system, yet also endothelial cells and multiple tissues/organ systems. Anti-SARS-CoV-2 directed cellular immune responses may be deleterious or may confer immune protection – more research is needed in order to link epitope-specific T-cell responses with clinically relevant endpoints.1 Analysis of epitope reactivity in blood from healthy individuals showed pre-existing (CD4+) reactivity most likely due to previous exposure to the common old coronavirus species HCoV-OC43, HCoV-229E, - NL63 or HKU1, or – not mutually exclusive - cross-reactive T-cell responses that would recognize SARS-CoV-2, yet also other non-SARS-CoV-2 targets.2,3 Detailed single cell analysis in PBMCs from patients with COVID-19 showed strong T-cell activation and expansion of TCR gamma – delta T-cells in patients with fast recovery or mild clinical symptoms.4 Previous studies examining antigen-specific T-cell responses in tumor-infiltrating T-cells (TIL) showed that EBV or CMV-specific cellular immune responses in TIL from patients with melanoma or pancreatic cancer. Such virus -specific T-cells may represent ‘bystander’ T-cell activation, yet they may also impact on the quality and quantity of anti-tumor directed immune responses. We tested therefore TIL expanded from 5 patients with gastrointestinal cancer, who underwent elective tumor surgery during the COVID-19 pandemic for recognition of a comprehensive panel of SARS-CoV-2 T-cell epitopes and compared the reactivity, defined by IFN-gamma production to TIL reactivity in TIL harvested from patients in 2018, prior to the pandemic.MethodsA set of 187 individual T-cell epitopes were tested for TIL recognition using 100IU IL-2 and 100 IU IL-15. Different peptide epitopes were selected: i) all epitopes were not shared with the 4 common old coronavirus species, ii) some peptides were unique for SARS-CoV-2, and iii) others were shared with SARS-CoV-1. Antigen targets were either 15 mers or 9mers for MHC class II or class I epitopes, respectively, derived from the nucleocapsid, membrane, spike protein, ORF8 or the ORF3a. The amount of IFN-gamma production was reported as pg/10e4 cells/epitope/5 days. Controls included CMV and EBV peptides.ResultsWe detected strong IFN-gamma production directed against antigenic ‘hotspots’ including the ORF3a, epitopes from the SARS-CoV-2 nucleocapsid and spike protein with a range of 12 up to 30 targets being recognized/TIL.ConclusionsSARS-CoV-2 epitope recognition, defined by IFN production, can be readily detected in TIL from patients who underwent surgery during the pandemic, which is not the case for TIL harvested prior to the circulating SARS-CoV-2. This suggests a broader exposure of individuals to SARS-CoV-2 and shows that SARS-CoV-2 responses may shape the quality and quantity of anti-cancer directed cellular immune responses in patients with solid epithelial malignancies.AcknowledgementsWe thank the Surgery, Pathology and Vivarium Units of Champalimaud Clinical Center (N. Figueiredo, A. Brandl, A. Beltran, M. Castillo, C. Silva ).Ethics ApprovalThis study was approved by the Champalimaud Foundation Ethics Committee.ConsentAll donors provided written consent and the study was approved by the local ethics committee. The study is in compliance with the Declaration of Helsinki.ReferencesGrifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., Rawlings, S. A., Sutherland, A., Premkumar, L., Jadi, R. S., Marrama, D., de Silva, A. M., Frazier, A., Carlin, A. F., Greenbaum, J. A., Peters, B., Krammer, F., Smith, D. M., Crotty, S., & Sette, A. ( 2020). Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell, 181(7), 1489–1501.e15. https://doi.org/10.1016/j.cell.2020.05.015Mateus, J., Grifoni, A., Tarke, A., Sidney, J., Ramirez, S. I., Dan, J. M., Burger, Z. C., Rawlings, S. A., Smith, D. M., Phillips, E., Mallal, S., Lammers, M., Rubiro, P., Quiambao, L., Sutherland, A., Yu, E. D., da Silva Antunes, R., Greenbaum, J., Frazier, A., … Weiskopf, D. ( 2020). Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science, eabd3871. https://doi.org/10.1126/science.abd3871Le Bert, N., Tan, A. T., Kunasegaran, K., Tham, C. Y. L., Hafezi, M., Chia, A., Chng, M. H. Y., Lin, M., Tan, N., Linster, M., Chia, W. N., Chen, M. I.-C., Wang, L.-F., Ooi, E. E., Kalimuddin, S., Tambyah, P. A., Low, J. G.-H., Tan, Y.-J., & Bertoletti, A. ( 2020). SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature, 584(7821), 457–462. https://doi.org/10.1038/s41586-020-2550-zZhang, J., Wang, X., Xing, X. et al. Single-cell landscape of immunological responses in patients with COVID-19. Nat Immunol 2020;21:1107–1118. https://doi.org/10.1038/s41590-020-0762-x

Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

2018 ◽  
Author(s):  
Hachemi Kadri ◽  
Taher E. Taher ◽  
Qin Xu ◽  
Richard T. Bryan ◽  
Benjamin E. Willcox ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Serum Stability ◽  
T Cell Immune Responses ◽  
Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

2018 ◽  
Author(s):  
Hachemi Kadri ◽  
Taher E. Taher ◽  
Qin Xu ◽  
Richard T. Bryan ◽  
Benjamin E. Willcox ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Serum Stability ◽  
T Cell Immune Responses ◽  
Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

Prediction of Prophylactic Peptide Vaccine Candidates for Human Papillomavirus (HPV): An Immunoinformatics and Reverse Vaccinology Approach

2020 ◽  
Vol 17 ◽  
Author(s):  
Mehreen Ismail ◽  
Zureesha Sajid ◽  
Amjad Ali ◽  
Xiaogang Wu ◽  
Syed Aun Muhammad ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
Binding Affinity ◽  
Cd8 T Cells ◽  
Reverse Vaccinology ◽  
Host Immune System ◽  
T Cell Epitopes ◽  
Multiple Alleles ◽  
Vaccine Candidates

Background: Human Papillomavirus (HPV) is responsible for substantial morbidity and mortality worldwide. We predicted immunogenic promiscuous monovalent and polyvalent T-cell epitopes from the polyprotein of the Human Papillomavirus (HPV) using a range of bioinformatics tools and servers. Methods: We used immunoinformatics and reverse vaccinology-based approaches to design prophylactic peptides by antigenicity analysis, Tcell epitopes prediction, proteasomal and conservancy evaluation, host-pathogen protein interactions, and in silico binding affinity analysis. Results: We found two early proteins (E2 and E6) and two late proteins (L1 and L2) of HPV as potential vaccine candidates. Of these proteins (E2, E6, L1 & L2), 2-epitopes of each candidate protein for multiple alleles of MHC class I and II bearing significant binding affinity (>-6.0 kcal/mole). These potential epitopes for CD4+ and CD8+ T-cells were also linked to design polyvalent construct using GPGPG linkers. Cholera toxin B and mycobacterial heparin-binding hemagglutinin adjuvant with a molecular weight of 12.5 and 18.5 kDa were used for epitopes of CD4+ and CD8+ T-cells respectively. The molecular docking indicated the optimum binding affinity of HPV peptides with MHC molecules. This interaction showed that our predicted vaccine candidates are suitable to trigger the host immune system to prevent HPV infections. Conclusion: The predicted conserved T-cell epitopes would contribute to the imminent design of HPV vaccine candidates, which will be able to induce a broad range of immune-responses in a heterogeneous HLA population.

Sign in / Sign up

Export Citation Format

Share Document