scholarly journals Computational Eurotransplant kidney allocation simulations demonstrate the feasibility and benefit of T-cell epitope matching

2021 ◽  
Vol 17 (7) ◽  
pp. e1009248
Author(s):  
Matthias Niemann ◽  
Nils Lachmann ◽  
Kirsten Geneugelijk ◽  
Eric Spierings
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Haplotype Frequency ◽  
Deceased Donor ◽  
Waiting List ◽  
T Cell Epitopes ◽  
Kidney Allocation ◽  
Virtual Population ◽  
Considerable Impact ◽  
The Impact

The EuroTransplant Kidney Allocation System (ETKAS) aims at allocating organs to patients on the waiting list fairly whilst optimizing HLA match grades. ETKAS currently considers the number of HLA-A, -B, -DR mismatches. Evidently, epitope matching is biologically and clinically more relevant. We here executed ETKAS-based computer simulations to evaluate the impact of epitope matching on allocation and compared the strategies. A virtual population of 400,000 individuals was generated using the National Marrow Donor Program (NMDP) haplotype frequency dataset of 2011. Using this population, a waiting list of 10,400 patients was constructed and maintained during simulation, matching the 2015 Eurotransplant Annual Report characteristics. Unacceptable antigens were assigned randomly relative to their frequency using HLAMatchmaker. Over 22,600 kidneys were allocated in 10 years in triplicate using Markov Chain Monte Carlo simulations on 32-CPU-core cloud-computing instances. T-cell epitopes were calculated using the www.pirche.com portal. Waiting list effects were evaluated against ETKAS for five epitope matching scenarios. Baseline simulations of ETKAS slightly overestimated reported average HLA match grades. The best balanced scenario maintained prioritisation of HLA A-B-DR fully matched donors while replacing the HLA match grade by PIRCHE-II score and exchanging the HLA mismatch probability (MMP) by epitope MMP. This setup showed no considerable impact on kidney exchange rates and waiting time. PIRCHE-II scores improved, whereas the average HLA match grade diminishes slightly, yet leading to an improved estimated graft survival. We conclude that epitope-based matching in deceased donor kidney allocation is feasible while maintaining equal balances on the waiting list.

scholarly journals Viral population genomics reveals host and infectivity impact on SARS-CoV-2 adaptive landscape

2021 ◽  
Author(s):  
Kaitlyn Gayvert ◽  
Richard Copin ◽  
Sheldon McKay ◽  
Ian Setliff ◽  
Wei Keat Lim ◽  
...  
Keyword(s):  
T Cell ◽  
Population Genomics ◽  
Cell Epitope ◽  
Purifying Selection ◽  
Spike Protein ◽  
Viral Population ◽  
Adaptive Landscape ◽  
T Cell Epitopes ◽  
Treatment Development ◽  
The Impact

Public health surveillance, drug treatment development, and optimization of immunological interventions all depend on understanding pathogen adaptation, which differ for specific pathogens. SARS-CoV-2 is an exceptionally successful human pathogen, yet complete understanding of the forces driving its evolution is lacking. Here, we leveraged almost four million SARS-CoV-2 sequences originating mostly from non-vaccinated naive patients to investigate the impact of functional constraints and natural immune pressures on the sequence diversity of the SARS-CoV-2 genome. Overall, we showed that the SARS-CoV-2 genome is under strong and intensifying levels of purifying selection with a minority of sites under diversifying pressure. With a particular focus on the spike protein, we showed that sites under selection were critical for protein stability and virus fitness related to increased infectivity and/or reduced neutralization by convalescent sera. We investigated the genetic diversity of SARS-CoV-2 B and T cell epitopes and determined that the currently known T cell epitope sequences were highly conserved. Outside of the spike protein, we observed that mutations under selection in variants of concern can be associated to beneficial outcomes for the virus. Altogether, the results yielded a comprehensive map of all sites under selection across the entirety of SARS-CoV-2 genome, highlighting targets for future studies to better understand the virus spread, evolution and success.

scholarly journals Immunodominance in Mouse and Human CD4+ T-Cell Responses Specific for the Bordetella pertussis Virulence Factor P.69 Pertactin

2008 ◽  
Vol 77 (2) ◽  
pp. 896-903 ◽  
Author(s):  
Rachel M. Stenger ◽  
Martien C. M. Poelen ◽  
Ed E. Moret ◽  
Betsy Kuipers ◽  
Sven C. M. Bruijns ◽  
...  
Keyword(s):  
T Cell ◽  
Bordetella Pertussis ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Cell Immunity ◽  
Hla Dq ◽  
Natural Variants ◽  
Acellular Vaccines

ABSTRACT P.69 pertactin (P.69 Prn), an adhesion molecule from the causative agent of pertussis, Bordetella pertussis, is present in cellular and most acellular vaccines that are currently used worldwide. Although both humoral immunity and cellular immunity directed against P.69 Prn have been implicated in protective immune mechanisms, the identities of CD4+ T-cell epitopes on the P.69 Prn protein remain unknown. Here, a single I-Ad-restricted B. pertussis conserved CD4+ T-cell epitope at the N terminus of P.69 Prn was identified by using a BALB/c T-cell hybridoma. The epitope appeared immunodominant among four other minor strain-conserved P.69 Prn epitopes recognized after vaccination and B. pertussis infection, and it was capable of evoking a Th1/Th17-type cytokine response. B. pertussis P.69 Prn immune splenocytes did not cross-react with natural variants of the epitope as present in Bordetella parapertussis and Bordetella bronchiseptica. Finally, it was found that the immunodominant P.69 Prn epitope is broadly recognized in the human population by CD4+ T cells in an HLA-DQ-restricted manner. During B. pertussis infection, the epitope was associated with a Th1-type CD4+ T-cell response. Hence, this novel P.69 Prn epitope is involved in CD4+ T-cell immunity after B. pertussis vaccination and infection in mice and, more importantly, in humans. Thus, it may provide a useful tool for the evaluation of the type, magnitude, and maintenance of B. pertussis-specific CD4+ T-cell mechanisms in preclinical and clinical vaccine studies.

scholarly journals Vaccination With a FAT1-Derived B Cell Epitope Combined With Tumor-Specific B and T Cell Epitopes Elicits Additive Protection in Cancer Mouse Models

2018 ◽  
Vol 8 ◽  
Author(s):  
Alberto Grandi ◽  
Laura Fantappiè ◽  
Carmela Irene ◽  
Silvia Valensin ◽  
Michele Tomasi ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Mouse Models ◽  
Cell Epitope ◽  
T Cell Epitopes ◽  
B Cell Epitope

scholarly journals Mining the capacity of human-associated microorganisms to trigger rheumatoid arthritis—A systematic immunoinformatics analysis of T cell epitopes

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253918
Author(s):  
Jelena Repac ◽  
Marija Mandić ◽  
Tanja Lunić ◽  
Bojan Božić ◽  
Biljana Božić Nedeljković
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
De Novo ◽  
Molecular Mimicry ◽  
Sequence Similarity ◽  
Cell Epitope ◽  
Homology Search ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Painful Condition

Autoimmune diseases, often triggered by infection, affect ~5% of the worldwide population. Rheumatoid Arthritis (RA)–a painful condition characterized by the chronic inflammation of joints—comprises up to 20% of known autoimmune pathologies, with the tendency of increasing prevalence. Molecular mimicry is recognized as the leading mechanism underlying infection-mediated autoimmunity, which assumes sequence similarity between microbial and self-peptides driving the activation of autoreactive lymphocytes. T lymphocytes are leading immune cells in the RA-development. Therefore, deeper understanding of the capacity of microorganisms (both pathogens and commensals) to trigger autoreactive T cells is needed, calling for more systematic approaches. In the present study, we address this problem through a comprehensive immunoinformatics analysis of experimentally determined RA-related T cell epitopes against the proteomes of Bacteria, Fungi, and Viruses, to identify the scope of organisms providing homologous antigenic peptide determinants. By this, initial homology screening was complemented with de novo T cell epitope prediction and another round of homology search, to enable: i) the confirmation of homologous microbial peptides as T cell epitopes based on the predicted binding affinity to RA-related HLA polymorphisms; ii) sequence similarity inference for top de novo T cell epitope predictions to the RA-related autoantigens to reveal the robustness of RA-triggering capacity for identified (micro/myco)organisms. Our study reveals a much larger repertoire of candidate RA-triggering organisms, than previously recognized, providing insights into the underestimated role of Fungi in autoimmunity and the possibility of a more direct involvement of bacterial commensals in RA-pathology. Finally, our study pinpoints Endoplasmic reticulum chaperone BiP as the most potent (most likely mimicked) RA-related autoantigen, opening an avenue for identifying the most potent autoantigens in a variety of different autoimmune pathologies, with possible implications in the design of next-generation therapeutics aiming to induce self-tolerance by affecting highly reactive autoantigens.

scholarly journals The Antigenic Topology of Norovirus as Defined by B and T Cell Epitope Mapping: Implications for Universal Vaccines and Therapeutics

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 432 ◽  
Author(s):  
Jessica M. van Loben Sels ◽  
Kim Y. Green
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
T Cell Epitopes ◽  
B Cell Epitopes ◽  
P Domain ◽  
Capsid Protein Vp1 ◽  
Murine Noroviruses ◽  
Acute Nonbacterial Gastroenteritis ◽  
Insight Into

Human norovirus (HuNoV) is the leading cause of acute nonbacterial gastroenteritis. Vaccine design has been confounded by the antigenic diversity of these viruses and a limited understanding of protective immunity. We reviewed 77 articles published since 1988 describing the isolation, function, and mapping of 307 unique monoclonal antibodies directed against B cell epitopes of human and murine noroviruses representing diverse Genogroups (G). Of these antibodies, 91, 153, 21, and 42 were reported as GI-specific, GII-specific, MNV GV-specific, and G cross-reactive, respectively. Our goal was to reconstruct the antigenic topology of noroviruses in relationship to mapped epitopes with potential for therapeutic use or inclusion in universal vaccines. Furthermore, we reviewed seven published studies of norovirus T cell epitopes that identified 18 unique peptide sequences with CD4- or CD8-stimulating activity. Both the protruding (P) and shell (S) domains of the major capsid protein VP1 contained B and T cell epitopes, with the majority of neutralizing and HBGA-blocking B cell epitopes mapping in or proximal to the surface-exposed P2 region of the P domain. The majority of broadly reactive B and T cell epitopes mapped to the S and P1 arm of the P domain. Taken together, this atlas of mapped B and T cell epitopes offers insight into the promises and challenges of designing universal vaccines and immunotherapy for the noroviruses.

scholarly journals Computer-Aided Design of an Epitope-Based Vaccine against Epstein-Barr Virus

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Julio Alonso-Padilla ◽  
Esther M. Lafuente ◽  
Pedro A. Reche
Keyword(s):  
T Cell ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Epitope ◽  
T Cell Epitopes ◽  
Cell Component ◽  
B Cell Epitopes ◽  
Barr Virus ◽  
Epstein Barr ◽  
Epitope Selection

Epstein-Barr virus is a very common human virus that infects 90% of human adults. EBV replicates in epithelial and B cells and causes infectious mononucleosis. EBV infection is also linked to various cancers, including Burkitt’s lymphoma and nasopharyngeal carcinomas, and autoimmune diseases such as multiple sclerosis. Currently, there are no effective drugs or vaccines to treat or prevent EBV infection. Herein, we applied a computer-aided strategy to design a prophylactic epitope vaccine ensemble from experimentally defined T and B cell epitopes. Such strategy relies on identifying conserved epitopes in conjunction with predictions of HLA presentation for T cell epitope selection and calculations of accessibility and flexibility for B cell epitope selection. The T cell component includes 14 CD8 T cell epitopes from early antigens and 4 CD4 T cell epitopes, targeted during the course of a natural infection and providing a population protection coverage of over 95% and 81.8%, respectively. The B cell component consists of 3 experimentally defined B cell epitopes from gp350 plus 4 predicted B cell epitopes from other EBV envelope glycoproteins, all mapping in flexible and solvent accessible regions. We discuss the rationale for the formulation and possible deployment of this epitope vaccine ensemble.

scholarly journals T-Cell Epitopes in Severe Acute Respiratory Syndrome (SARS) Coronavirus Spike Protein Elicit a Specific T-Cell Immune Response in Patients Who Recover from SARS

2004 ◽  
Vol 78 (11) ◽  
pp. 5612-5618 ◽  
Author(s):  
Yue-Dan Wang ◽  
Wan-Yee Fion Sin ◽  
Guo-Bing Xu ◽  
Huang-Hua Yang ◽  
Tin-yau Wong ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
T Cell Response ◽  
Cell Immune Response ◽  
T Cell Epitopes ◽  
Online Database ◽  
Database Analysis ◽  
S Protein ◽  
Healthy Donors ◽  
Ifn Γ

ABSTRACT The immunogenicity of HLA-A2-restricted T-cell epitopes in the S protein of the Severe acute respiratory syndrome coronavirus (SARS-CoV) and of human coronavirus strain 229e (HCoV-229e) was analyzed for the elicitation of a T-cell immune response in donors who had fully recovered from SARS-CoV infection. We employed online database analysis to compare the differences in the amino acid sequences of the homologous T epitopes of HCoV-229e and SARS-CoV. The identified T-cell epitope peptides were synthesized, and their binding affinities for HLA-A2 were validated and compared in the T2 cell system. The immunogenicity of all these peptides was assessed by using T cells obtained from donors who had fully recovered from SARS-CoV infection and from healthy donors with no history of SARS-CoV infection. HLA-A2 typing by indirect immunofluorescent antibody staining showed that 51.6% of SARS-CoV-infected patients were HLA-A2 positive. Online database analysis and the T2 cell binding test disclosed that the number of HLA-A2-restricted immunogenic epitopes of the S protein of SARS-CoV was decreased or even lost in comparison with the homologous sequences of the S protein of HCoV-229e. Among the peptides used in the study, the affinity of peptides from HCoV-229e (H77 and H881) and peptides from SARS-CoV (S978 and S1203) for binding to HLA-A2 was higher than that of other sequences. The gamma interferon (IFN-γ) release Elispot assay revealed that only SARS-CoV-specific peptides S1203 and S978 induced a high frequency of IFN-γ-secreting T-cell response in HLA-A2+ donors who had fully recovered from SARS-CoV infection; such a T-cell epitope-specific response was not observed in HLA-A2+ healthy donors or in HLA-A2− donors who had been infected with SARS-CoV after full recovery. Thus, T-cell epitopes S1203 and S978 are immunogenic and elicit an overt specific T-cell response in HLA-A2+ SARS-CoV-infected patients.

scholarly journals In Silico Identification and in Vitro Analysis of B and T-Cell Epitopes of the Black Turtle Bean (Phaseolus Vulgaris L.) Lectin

2018 ◽  
Vol 49 (4) ◽  
pp. 1600-1614 ◽  
Author(s):  
Shudong He ◽  
Jinlong Zhao ◽  
Walid Elfalleh ◽  
Mohamed Jemaà ◽  
Hanju  Sun ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cell ◽  
Phaseolus Vulgaris ◽  
B Cell ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Phaseolus Vulgaris L ◽  
B Cell Epitopes ◽  
B Cell Epitope

Background/Aims: The incidence of lectin allergic disease is increasing in recent decades, and definitive treatment is still lacking. Identification of B and T-cell epitopes of allergen will be useful in understanding the allergen antibody responses as well as aiding in the development of new diagnostics and therapy regimens for lectin poisoning. In the current study, we mainly addressed these questions. Methods: Three-dimensional structure of the lectin from black turtle bean (Phaseolus vulgaris L.) was modeled using the structural template of Phytohemagglutinin from P. vulgaris (PHA-E, PDB ID: 3wcs.1.A) with high identity. The B and T-cell epitopes were screened and identified by immunoinformatics and subsequently validated by ELISA, lymphocyte proliferation and cytokine profile analyses. Results: Seven potential B-cell epitopes (B1 to B7) were identified by sequence and structure based methods, while three T-cell epitopes (T1 to T3) were identified by the predictions of binding score and inhibitory concentration. The epitope peptides were synthesized. Significant IgE binding capability was found in B-cell epitopes (B2, B5, B6 and B7) and T2 (a cryptic B-cell epitope). T1 and T2 induced significant lymphoproliferation, and the release of IL-4 and IL-5 cytokine confirmed the validity of T-cell epitope prediction. Abundant hydrophobic amino acids were found in B-cell epitope and T-cell epitope regions by amino acid analysis. Positively charged amino acids, such as His residue, might be more favored for B-cell epitope. Conclusion: The present approach can be applied for the identification of epitopes in novel allergen proteins and thus for designing diagnostics and therapies in lectin allergy.

scholarly journals Autodisplay

2003 ◽  
Vol 71 (11) ◽  
pp. 6320-6328 ◽  
Author(s):  
Konstantin Rizos ◽  
Claus T. Lattemann ◽  
Dirk Bumann ◽  
Thomas F. Meyer ◽  
Toni Aebischer
Keyword(s):  
T Cell ◽  
Oral Vaccine ◽  
Expression System ◽  
Surface Display ◽  
Cell Epitope ◽  
T Cell Epitopes ◽  
T Helper ◽  
Serovar Typhimurium ◽  
A Subunit ◽  
H Pylori

ABSTRACT Live attenuated Salmonella strains expressing antigens of pathogens are promising oral vaccine candidates. There is growing evidence that the topology of expression of the foreign antigens can have a dramatic impact on the immunogenicity. We examined the potential of the AIDA-I (Escherichia coli adhesin involved in diffuse adherence) autotransporter domain to display antigenic fragments of the urease A subunit of Helicobacter pylori for the induction of a protective immune response. In the murine H. pylori model, protection is mainly mediated by CD4+ T cells, and we therefore used the AIDA-I expression system to successfully express both nearly full-length UreA and defined T-helper-cell epitopes on the surface of an attenuated Salmonella enterica serovar Typhimurium vaccine strain. Surface exposure of the large UreA fragment or of one UreA T-cell epitope mediated a significant reduction in the level of H. pylori in immunized mice after challenge infection, whereas conventional cytoplasmic expression of UreA in Salmonella had no effect. These results support the concept that surface display increases the immunogenicity of recombinant antigens expressed on oral live vaccine carriers and further demonstrate the feasibility of immunizing against H. pylori with Salmonella vaccine strains expressing CD4+ T-cell epitopes.

Sign in / Sign up

Export Citation Format

Share Document