scholarly journals Relationship between Thyroid Peroxidase T Cell Epitope Restriction and Antibody Recognition of the Autoantibody Immunodominant Region in Human Leukocyte Antigen DR3 Transgenic Mice

Endocrinology ◽  
2005 ◽  
Vol 146 (11) ◽  
pp. 4961-4967 ◽  
Author(s):  
Jin Guo ◽  
Sandra M. McLachlan ◽  
Pavel N. Pichurin ◽  
Chun-Rong Chen ◽  
Nancy Pham ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
Thyroid Autoimmunity ◽  
Cell Epitope ◽  
Class Ii ◽  
Human Thyroid ◽  
Thyroid Peroxidase ◽  
T Cell Epitopes ◽  
Immunodominant Region

We investigated the relationship between thyroid peroxidase (TPO) antibody and T lymphocyte epitopes in TPO-adenovirus (TPO-Ad) immunized BALB/c mice and mice transgenic for the human class II molecule DR3 associated with human thyroid autoimmunity. TPO autoantibodies are largely restricted to an immunodominant region (IDR). BALB/c mice immunized with fewer (107vs. 109) TPO-Ad particles developed TPO antibodies with lower titers that displayed greater restriction to the IDR. However, as with higher-dose TPO-Ad immunization, T cell epitopes (assessed by splenocyte interferon-γ response to TPO in vitro) were highly diverse and variable in different animals. In contrast, DR3 mice immunized the higher TPO-Ad dose (109 particles) had high TPO antibody levels that showed relative focus on the IDR. Moreover, T cell epitopes recognized by splenocytes from DR3 mice showed greater restriction than BALB/c mice. Antibody affinities for TPO were higher in DR3 than in BALB/c mice. The present study indicates that weak TPO-Ad immunization of BALB/c mice (with consequent low TPO antibody titers) is required for enhanced IDR focus yet is not associated with T cell epitopic restriction. Humanized DR3 transgenic mice, despite stronger TPO-Ad immunization, develop higher titer TPO antibodies that do focus on the autoantibody IDR with T cells that recognize a more limited range of TPO peptides. These data suggest a relationship between major histocompatibility complex class II molecules and the development of antibodies to the IDR, a feature of human thyroid autoimmunity.

scholarly journals Construction and Evaluation of a Novel Recombinant T Cell Epitope-Based Vaccine against Coccidioidomycosis

2012 ◽  
Vol 80 (11) ◽  
pp. 3960-3974 ◽  
Author(s):  
Brady J. Hurtgen ◽  
Chiung-Yu Hung ◽  
Gary R. Ostroff ◽  
Stuart M. Levitz ◽  
Garry T. Cole
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cell Epitope ◽  
T Cell Epitopes ◽  
Protein Vaccine ◽  
T Helper 1 ◽  
Human Major Histocompatibility Complex ◽  
Content Type ◽  
Mhc Ii

ABSTRACTClinical and animal studies of coccidioidomycosis have demonstrated that activated CD4+T lymphocytes are essential for protection against this fungal respiratory disease. We previously reported a vaccine againstCoccidioidesinfection which contained three recombinant CD4+T cell-reactive proteins and induced a robust, protective immune response in mice. Due to the anticipated high cost of production and clinical assessment of this multivalent vaccine, we generated a single protein which contained immunodominant T cell epitopes of the three polypeptides. Epitopes were initially identified by computational prediction of their ability to bind promiscuously to human major histocompatibility complex class II (MHC II) molecules. Cellular immunoassays confirmed the immunogenicity of the synthesized epitope peptides, whilein vitrobinding assays revealed a range of peptide affinity for MHC II. A DNA construct was synthesized for bacterial expression of a recombinant protein vaccine which contained five epitopes with the highest affinity for human MHC II, each fused with leader and spacer peptides proposed to optimize epitope processing and presentation to T cell receptors. Recall assays of immune T lymphocytes obtained from human MHC II-expressing HLA-DR4 transgenic mice confirmed that 4 of the 5 epitope peptides were processed. Mice immunized with the epitope-based vaccine admixed with a synthetic oligodeoxynucleotide adjuvant or loaded into yeast glucan particles and then challenged intranasally withCoccidioidesshowed early lung infiltration of activated T helper-1 (Th1), Th2, and Th17 cells, elevated gamma interferon (IFN-γ) and interleukin (IL)-17 production, significant reduction of fungal burden, and prolongation of survival compared to nonvaccinated mice. This is the first report of an epitope-based vaccine against coccidioidomycosis.

scholarly journals Screening of HLA-A restricted T cell epitopes of SARS-CoV-2 and induction of CD8+ T cell responses in HLA-A transgenic mice

2021 ◽  
Author(s):  
Xiaoxiao Jin ◽  
Ding Yan ◽  
Sun Shihui ◽  
Xinyi Wang ◽  
Zining Zhou ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
Cell Epitope ◽  
T Cell Responses ◽  
Poly I:C ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Mhc Class I Molecule ◽  
Healthy Donors ◽  
Epitope Vaccines

AbstractWhile SARS-CoV-2-specific T cells have been characterized to play essential roles in host immune protection in COVID-19 patients, few researches focus on the functional validation of T cell epitopes and development of vaccines inducing specific T cell responses. In this study, 120 CD8+ T cell epitopes from E, M, N, S and RdRp proteins of SARS-CoV-2 were validated by on-silicon prediction, DC-peptide-PBL costimulation with healthy donors’ PBMCs and HLA-A molecule competitive binding experiments. Among them, 110, 15, 6, 14 and 12 epitopes were highly homologous with SARS-CoV, OC43, NL63, HKU1, and 229E, respectively. Thirty-one epitopes restricted by HLA-A2 molecule were used to generate peptide cocktail vaccines in combination with Poly(I:C), R848 or polylactic-co-glycolic acid nanoparticles, which elicited robust specific CD8+ T cell responses in wild-type and HLA-A2/DR1 transgenic mice. Seven of the 31 epitopes were found to be cross-presented by HLA-A2 and H-2K/Db molecules. These data have provided a library of SARS-CoV-2 CD8+ T cell epitopes which restricted by a series of high-frequency HLA-A allotypes and covered broad population in Asia, and initially confirmed the feasibility of human MHC class I molecule-restricted SARS-CoV2 epitope peptide cocktail vaccines, thus will facilitate the development of T cell epitope vaccines and specific cellular function detection kits.

scholarly journals Construction and efficacy evaluation of novel swine leukocyte antigen (SLA) class I and class II allele-specific poly-T cell epitope vaccines against porcine reproductive and respiratory syndrome virus

2020 ◽  
Vol 101 (11) ◽  
pp. 1191-1201
Author(s):  
Debin Tian ◽  
Sakthivel Subramaniam ◽  
C. Lynn Heffron ◽  
Hassan M. Mahsoub ◽  
Harini Sooryanarain ◽  
...  
Keyword(s):  
T Cell ◽  
Statistical Significance ◽  
Cell Epitope ◽  
Class Ii ◽  
Class I ◽  
Respiratory Syndrome Virus ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Efficacy Evaluation ◽  
Allele Specific

Porcine reproductive and respiratory syndrome virus (PRRSV) causes an economically important global swine disease. Here we report the development of subunit PRRSV-2 vaccines by expressing swine leucocyte antigen (SLA) class I and class II allele-specific epitope antigens in a robust adenovirus vector. SLA I-specific CD8 and SLA II-specific CD4 T cell epitopes of PRRSV-2 NADC20 were predicted in silico. Stable murine leukaemia cell lines (RMA-S), which are TAP-deficient and lacking endogenous class I epitope loading, were established to express different SLA I alleles. The binding stability of PRRSV T cell epitope peptides with SLA I alleles expressed on RMA-S cells was characterized. Two PRRSV poly-T cell epitope peptides were designed. NADC20-PP1 included 39 class I epitopes, consisting of 8 top-ranked epitopes specific to each of 5 SLA I alleles, and fused to 5 class II epitopes specific to SLA II alleles. NADC20-PP2, a subset of PP1, included two top-ranked class I epitopes specific to each of the five SLA I alleles. Two vaccine candidates, Ad-NADC20-PP1 and Ad-NADC20-PP2, were constructed by expressing the polytope peptides in a replication-incompetent human adenovirus 5 vector. A vaccination and challenge study in 30 piglets showed that animals vaccinated with the vaccines had numerically lower gross and histopathology lung lesions, and numerically lower PRRSV RNA loads in lung and serum after challenge compared to the controls, although there was no statistical significance. The results suggested that the Ad-NADC20-PP1 and Ad-NADC20-PP2 vaccines provided little or no protection, further highlighting the tremendous challenges faced in developing an effective subunit PRRSV-2 vaccine.

scholarly journals T Cell Epitope-Based Vaccine Design for Pandemic Novel Coronavirus 2019-nCoV

2020 ◽  
Author(s):  
Dr. Seema Mishra
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Structural Proteins ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Consensus Sequences ◽  
Tight Cluster ◽  
Cell Assays ◽  
Novel Coronavirus

Immunoinformatics approach has been used to identify potential T cell epitopes from structural and non-structural proteins for immunotherapy against novel coronavirus 2019-nCoV across populations Two different prediction algorithms, NetCTLpan and Pickpocket were used to generate consensus epitopes against HLA supertypes. All of the 57 epitopes identified had no similarity/identity with the human proteome thus preventing crossreactivity. Many of these epitopes formed a tight cluster around consensus sequences <p>MGYINVFAFPFTIYSLLLC and KVSIWNLDYIINLI across proteins and alleles. These should be urgently tested in <i>in-vitro</i> MHC binding and T cell assays before being tried as vaccines to further prevent pandemic due to this lethal coronavirus.<br></p>

scholarly journals Immunogenicity of a Recombinant Influenza Virus Bearing Both the CD4+ and CD8+ T Cell Epitopes of Ovalbumin

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Bruno Garulli ◽  
Giuseppina Di Mario ◽  
Ester Sciaraffia ◽  
Yoshihiro Kawaoka ◽  
Maria R. Castrucci
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
Influenza Viruses ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Additional Tool

Recombinant influenza viruses that bear the single immunodominant CD8+ T cell epitopeOVA257−264or the CD4+ T cell epitopeOVA323−339of the model antigen ovalbumin (OVA) have been useful tools in immunology. Here, we generated a recombinant influenza virus,WSN-OVAI/II, that bears both OVA-specific CD8+ and CD4+ epitopes on its hemagglutinin molecule. Live and heat-inactivatedWSN-OVAI/IIviruses were efficiently presented by dendritic cellsin vitroto OT-I TCR transgenic CD8+ T cells and OT-II TCR transgenic CD4+ T cells.In vivo,WSN-OVAI/IIvirus was attenuated in virulence, highly immunogenic, and protected mice from B16-OVA tumor challenge in a prophylactic model of vaccination. Thus,WSN-OVAI/IIvirus represents an additional tool, along with OVA TCR transgenic mice, for further studies on T cell responses and may be of value in vaccine design.

scholarly journals Identification of T-cell epitopes in the structural and non-structural proteins of classical swine fever virus

2002 ◽  
Vol 83 (3) ◽  
pp. 551-560 ◽  
Author(s):  
Elisenda Armengol ◽  
Karl-Heinz Wiesmüller ◽  
Daniel Wienhold ◽  
Mathias Büttner ◽  
Eberhard Pfaff ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
Classical Swine Fever Virus ◽  
Cell Epitope ◽  
Classical Swine Fever ◽  
Fever Virus ◽  
Target Cells ◽  
T Cell Epitopes ◽  
Structural Protein

To identify new T-cell epitopes of classical swine fever virus (CSFV), 573 overlapping, synthetic pentadecapeptides spanning 82% of the CSFV (strain Glentorf) genome sequence were synthesized and screened. In proliferation assays, 26 peptides distributed throughout the CSFV viral protein sequences were able to induce specific T-cell responses in PBMCs from a CSFV-Glentorf-infected d/d haplotype pig. Of these 26 peptides, 18 were also recognized by PBMCs from a CSFV-Alfort/187-infected d/d haplotype pig. In further experiments, it could be shown that peptide 290 (KHKVRNEVMVHWFDD), which corresponds to amino acid residues 1446–1460 of the CSFV non-structural protein NS2–3 could induce interferon-γ secretion after secondary in vitro restimulation. The major histocompatibility complex (MHC) restriction for stimulation of T-cells by this pentadecapeptide was identified as being mainly MHC class II and partially MHC class I. In cytolytic assays, CSFV-specific cytotoxic T-lymphocytes (CTLs) were able to lyse peptide 290-loaded target cells. These findings indicate the existence of a CSFV-specific helper T-cell epitope and a CTL epitope in this peptide.

scholarly journals Immune Tolerance-Adjusted Personalized Immunogenicity Prediction for Pompe Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Anne S. De Groot ◽  
Ankit K. Desai ◽  
Sandra Lelias ◽  
S. M. Shahjahan Miah ◽  
Frances E. Terry ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Outcomes ◽  
Pompe Disease ◽  
Clinical Decision Making ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
T Cell Epitopes ◽  
Enzyme Replacement ◽  
Hla Dr

Infantile-onset Pompe disease (IOPD) is a glycogen storage disease caused by a deficiency of acid alpha-glucosidase (GAA). Treatment with recombinant human GAA (rhGAA, alglucosidase alfa) enzyme replacement therapy (ERT) significantly improves clinical outcomes; however, many IOPD children treated with rhGAA develop anti-drug antibodies (ADA) that render the therapy ineffective. Antibodies to rhGAA are driven by T cell responses to sequences in rhGAA that differ from the individuals’ native GAA (nGAA). The goal of this study was to develop a tool for personalized immunogenicity risk assessment (PIMA) that quantifies T cell epitopes that differ between nGAA and rhGAA using information about an individual’s native GAA gene and their HLA DR haplotype, and to use this information to predict the risk of developing ADA. Four versions of PIMA have been developed. They use EpiMatrix, a computational tool for T cell epitope identification, combined with an HLA-restricted epitope-specific scoring feature (iTEM), to assess ADA risk. One version of PIMA also integrates JanusMatrix, a Treg epitope prediction tool to identify putative immunomodulatory (regulatory) T cell epitopes in self-proteins. Using the JanusMatrix-adjusted version of PIMA in a logistic regression model with data from 48 cross-reactive immunological material (CRIM)-positive IOPD subjects, those with scores greater than 10 were 4-fold more likely to develop ADA (p&lt;0.03) than those that had scores less than 10. We also confirmed the hypothesis that some GAA epitopes are immunomodulatory. Twenty-one epitopes were tested, of which four were determined to have an immunomodulatory effect on T effector response in vitro. The implementation of PIMA V3J on a secure-access website would allow clinicians to input the individual HLA DR haplotype of their IOPD patient and the GAA pathogenic variants associated with each GAA allele to calculate the patient’s relative risk of developing ADA, enhancing clinical decision-making prior to initiating treatment with ERT. A better understanding of immunogenicity risk will allow the implementation of targeted immunomodulatory approaches in ERT-naïve settings, especially in CRIM-positive patients, which may in turn improve the overall clinical outcomes by minimizing the development of ADA. The PIMA approach may also be useful for other types of enzyme or factor replacement therapies.

scholarly journals Yellow fever 17D as a vaccine vector for microbial CTL epitopes

2005 ◽  
Vol 201 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Deng Tao ◽  
Giovanna Barba-Spaeth ◽  
Urvashi Rai ◽  
Victor Nussenzweig ◽  
Charles M. Rice ◽  
...  
Keyword(s):  
T Cell ◽  
Yellow Fever ◽  
Cell Epitope ◽  
Parasite Burden ◽  
Plasmodium Yoelii ◽  
Yellow Fever Vaccine ◽  
T Cell Epitopes ◽  
High Level

The yellow fever vaccine 17D (17D) is safe, and after a single immunizing dose, elicits long-lasting, perhaps lifelong protective immunity. One of the major challenges facing delivery of human vaccines in underdeveloped countries is the need for multiple injections to achieve full efficacy. To examine 17D as a vector for microbial T cell epitopes, we inserted the H-2Kd–restricted CTL epitope of the circumsporozoite protein (CS) of Plasmodium yoelii between 17D nonstructural proteins NS2B and NS3. The recombinant virus, 17D-Py, was replication competent and stable in vitro and in vivo. A single subcutaneous injection of 105 PFU diminished the parasite burden in the liver by ∼70%. The high level of protection lasted between 4 and 8 wk after immunization, but a significant effect was documented even 24 wk afterwards. Thus, the immunogenicity of a foreign T cell epitope inserted into 17D mimics some of the remarkable properties of the human vaccine. Priming with 17D-Py followed by boosting with irradiated sporozoites conferred sterile immunity to 90% of the mice. This finding indicates that the immune response of vaccine-primed individuals living in endemic areas could be sustained and magnified by the bite of infected mosquitoes.

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